DNA Damage/Telomere Stress Induced Senescence (Homo sapiens)

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2, 9, 13, 18, 20...46, 1182012, 18, 22, 39, 66...10, 15, 28, 70, 107...18, 2018, 20, 8011818, 32, 4022, 36, 100, 12646, 8030, 71, 10121, 28, 107, 115, 12053, 65, 78, 9671, 1012, 9, 13118, 20, 3622, 36, 100, 126, 13213, 79cytosolnucleoplasmKAT5 CABIN1 Cyclin E:Cdk2complexesHIST1H2BJ NBN CDKN1B NBN HIST2H2AA3 p16-INK4aKAT5 NBN HMGA2 Shortened telomere dsDNARAD50 HIST1H1A ATM DNA Double StrandBreak ResponseTERF2IP Shortenedtelomere:MRNMRE11A TERF1 CDKN1A GeneTERF2 NBN HIST1H2BH ACD SAHFHIST1H2AD HIST1H1A HMGA1CyclinA:Cdk2:p21/p27complexASF1AG-strand Chromosome end with two additional single strand repeats and a subterminal loop - Telomeric ROS HIST1H1E HIST1H2BB HIST1H1B HIST1H2BC CCNE2 RAD50 Cyclin A:Cdk2complexASF1A HIST3H3 RAD50 MRE11A HIST1H4 Shortened telomereKAT5 MRE11A HIST1H1E RB1ATM Oncogene InducedSenescenceHIST1H1D TERF2 CDKN1A NBN Histone H1CDKN1A Gene Shortenedtelomere:MRN:Ac-K3016-ATM dimer:KAT5CDKN1AROSHIST1H2BM DNA double-strand break ends H2BFS Histone H1 boundchromatin DNAHIST1H2BA H2AFZ Ac-CoACCNA1 ADPMitotic G1-G1/SphasesDNA DSBs:MRNSenescence-Associated Secretory Phenotype (SASP)Cell CycleCheckpointsHIST1H1B gamma-ray KAT5 CCNA2 CDKN1B p-S15-TP53 Intrinsic Pathwayfor ApoptosisCCNE2 Shelterin complexCDK2 p-S15-TP53 alpha-particle HMGA2MRE11A CyclinE:Cdk2:p21/p27complexDNADSBs:MRN:p-S1981,Ac-K3016-ATM:KAT5CCNE1 CABIN1 RAD50 TERF2IP ASF1A MRE11A DSB inducing agentsDNA CDKN1B DNA DSBs:MRN:ATMdimer:KAT5ATM Extended AndProcessed TelomereEnd and AssociatedDNA Binding andPackaging ProteinComplex Folded IntoHigher OrderStructureNBN HIST1H2BK NBN UBN1 UBN1MRE11A H2AFB1 HIST1H1C KAT5DNA double-strand break ends CDKN1A HIST1H1C TINF2 MRNDNA double-strandbreak endsRAD50 HIST1H2BL TP53 TetramerEP400 ATPRAD50 CDKN1A p-S15-TP53 TetramerShortened telomere p-S15-TP53 CCNA1 H1F0 RAD50 HIST1H2BD TP53 CDK2 TINF2 CDK2 Shortened telomere HIST1H2AJ Ac-K3016-ATM RAF/MAP kinasecascadeHIRA MRE11A ATPCoA-SHADPCDK2 HIST1H2BN proton ATM dimer:KAT5HIST1H2AB HIST1H2BO CABIN1POT1 X-ray ATPNBN ACD CCNA2 HIRATERF1 HIRA Shortenedtelomere:MRN:ATMdimer:KAT5ADPDNA HIST1H1D CCNE1 DNADSBs:MRN:Ac-K3016-ATM dimer:KAT5p-S1981,Ac-K3016-ATMHIST3H2BB KAT5 H1F0 DNA double-strand break ends LMNB1Ac-K3016-ATM H2AFX EP400MRE11A HMGA1 p-S15-TP53Tetramer:CDKN1AGeneHIST1H2AC POT1 p-S1981,Ac-K3016-ATM DNA double-strand break ends HIRA:ASF1A:UBN1:CABIN1EP400:p-S15-TP53Tetramer:CDKN1AGeneRAD50 ligated C-strand Okazaki fragment beta-particle CDKN1A Gene p21/p27HIST2H2AC KAT5 Oxidative StressInduced SenescenceUBN1 HIST2H2BE 3, 7, 11, 24, 34...18, 2014, 25, 42, 54, 56...182331, 35, 48, 62, 72...118971201, 4-6, 8...3651, 63, 1242046


Description

Reactive oxygen species (ROS), whose concentration increases in senescent cells due to oncogenic RAS-induced mitochondrial dysfunction (Moiseeva et al. 2009) or due to environmental stress, cause DNA damage in the form of double strand breaks (DSBs) (Yu and Anderson 1997). In addition, persistent cell division fueled by oncogenic signaling leads to replicative exhaustion, manifested in critically short telomeres (Harley et al. 1990, Hastie et al. 1990). Shortened telomeres are no longer able to bind the protective shelterin complex (Smogorzewska et al. 2000, de Lange 2005) and are recognized as damaged DNA.

The evolutionarily conserved MRN complex, consisting of MRE11A (MRE11), RAD50 and NBN (NBS1) subunits, binds DSBs (Lee and Paull 2005) and shortened telomeres that are no longer protected by shelterin (Wu et al. 2007). Once bound to the DNA, the MRN complex recruits and activates ATM kinase (Lee and Paull 2005, Wu et al. 2007), leading to phosphorylation of ATM targets, including TP53 (p53) (Banin et al. 1998, Canman et al. 1998, Khanna et al. 1998). TP53, phosphorylated on serine S15 by ATM, binds the CDKN1A (also known as p21, CIP1 or WAF1) promoter and induces CDKN1A transcription (El-Deiry et al. 1993, Karlseder et al. 1999). CDKN1A inhibits the activity of CDK2, leading to G1/S cell cycle arrest (Harper et al. 1993, El-Deiry et al. 1993).<p>SMURF2 is upregulated in response to telomere attrition in human fibroblasts and induces senecscent phenotype through RB1 and TP53, independently of its role in TGF-beta-1 signaling (Zhang and Cohen 2004). The exact mechanism of SMURF2 involvement is senescence has not been elucidated. View original pathway at:Reactome.</div>

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  112. Seidel JJ, Graves BJ.; ''An ERK2 docking site in the Pointed domain distinguishes a subset of ETS transcription factors.''; PubMed Europe PMC Scholia
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  115. Depoortere F, Van Keymeulen A, Lukas J, Costagliola S, Bartkova J, Dumont JE, Bartek J, Roger PP, Dremier S.; ''A requirement for cyclin D3-cyclin-dependent kinase (cdk)-4 assembly in the cyclic adenosine monophosphate-dependent proliferation of thyrocytes.''; PubMed Europe PMC Scholia
  116. Zhang R, Chen W, Adams PD.; ''Molecular dissection of formation of senescence-associated heterochromatin foci.''; PubMed Europe PMC Scholia
  117. Bakkenist CJ, Kastan MB.; ''DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation.''; PubMed Europe PMC Scholia
  118. Moiseeva O, Mallette FA, Mukhopadhyay UK, Moores A, Ferbeyre G.; ''DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation.''; PubMed Europe PMC Scholia
  119. Yu TW, Anderson D.; ''Reactive oxygen species-induced DNA damage and its modification: a chemical investigation.''; PubMed Europe PMC Scholia
  120. Lim CJ, Zaug AJ, Kim HJ, Cech TR.; ''Reconstitution of human shelterin complexes reveals unexpected stoichiometry and dual pathways to enhance telomerase processivity.''; PubMed Europe PMC Scholia
  121. Cheng M, Sexl V, Sherr CJ, Roussel MF.; ''Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1).''; PubMed Europe PMC Scholia
  122. Niehof M, Streetz K, Rakemann T, Bischoff SC, Manns MP, Horn F, Trautwein C.; ''Interleukin-6-induced tethering of STAT3 to the LAP/C/EBPbeta promoter suggests a new mechanism of transcriptional regulation by STAT3.''; PubMed Europe PMC Scholia
  123. Wang X.; ''The expanding role of mitochondria in apoptosis.''; PubMed Europe PMC Scholia
  124. Smogorzewska A, van Steensel B, Bianchi A, Oelmann S, Schaefer MR, Schnapp G, de Lange T.; ''Control of human telomere length by TRF1 and TRF2.''; PubMed Europe PMC Scholia
  125. Mizukami Y, Yoshioka K, Morimoto S, Yoshida Ki.; ''A novel mechanism of JNK1 activation. Nuclear translocation and activation of JNK1 during ischemia and reperfusion.''; PubMed Europe PMC Scholia
  126. Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J.; ''Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.''; PubMed Europe PMC Scholia
  127. Zhang H, Cohen SN.; ''Smurf2 up-regulation activates telomere-dependent senescence.''; PubMed Europe PMC Scholia
  128. Uziel T, Lerenthal Y, Moyal L, Andegeko Y, Mittelman L, Shiloh Y.; ''Requirement of the MRN complex for ATM activation by DNA damage.''; PubMed Europe PMC Scholia
  129. Connell-Crowley L, Harper JW, Goodrich DW.; ''Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation.''; PubMed Europe PMC Scholia
  130. Jimi E, Ikebe T, Takahashi N, Hirata M, Suda T, Koga T.; ''Interleukin-1 alpha activates an NF-kappaB-like factor in osteoclast-like cells.''; PubMed Europe PMC Scholia
  131. Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK, Allshire RC.; ''Telomere reduction in human colorectal carcinoma and with ageing.''; PubMed Europe PMC Scholia
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  141. Wajapeyee N, Serra RW, Zhu X, Mahalingam M, Green MR.; ''Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7.''; PubMed Europe PMC Scholia
  142. Young AR, Narita M.; ''SASP reflects senescence.''; PubMed Europe PMC Scholia
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  144. Sun Y, Xu Y, Roy K, Price BD.; ''DNA damage-induced acetylation of lysine 3016 of ATM activates ATM kinase activity.''; PubMed Europe PMC Scholia
  145. Takai KK, Hooper S, Blackwood S, Gandhi R, de Lange T.; ''In vivo stoichiometry of shelterin components.''; PubMed Europe PMC Scholia
  146. Raingeaud J, Whitmarsh AJ, Barrett T, Dérijard B, Davis RJ.; ''MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway.''; PubMed Europe PMC Scholia
  147. Lee JH, Paull TT.; ''Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex.''; PubMed Europe PMC Scholia
  148. Dietrich N, Bracken AP, Trinh E, Schjerling CK, Koseki H, Rappsilber J, Helin K, Hansen KH.; ''Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus.''; PubMed Europe PMC Scholia
  149. Sgouras DN, Athanasiou MA, Beal GJ, Fisher RJ, Blair DG, Mavrothalassitis GJ.; ''ERF: an ETS domain protein with strong transcriptional repressor activity, can suppress ets-associated tumorigenesis and is regulated by phosphorylation during cell cycle and mitogenic stimulation.''; PubMed Europe PMC Scholia
  150. Lee JH, Paull TT.; ''ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114855view16:36, 25 January 2021ReactomeTeamReactome version 75
113301view11:37, 2 November 2020ReactomeTeamReactome version 74
112513view15:47, 9 October 2020ReactomeTeamReactome version 73
101425view11:30, 1 November 2018ReactomeTeamreactome version 66
100963view21:07, 31 October 2018ReactomeTeamreactome version 65
100500view19:41, 31 October 2018ReactomeTeamreactome version 64
100046view16:25, 31 October 2018ReactomeTeamreactome version 63
99598view14:59, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93864view13:41, 16 August 2017ReactomeTeamreactome version 61
93429view11:23, 9 August 2017ReactomeTeamreactome version 61
87144view18:53, 18 July 2016MkutmonOntology Term : 'DNA damage response pathway' added !
86520view09:20, 11 July 2016ReactomeTeamreactome version 56
83455view12:26, 18 November 2015ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ACD ProteinQ96AP0 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
ASF1A ProteinQ9Y294 (Uniprot-TrEMBL)
ASF1AProteinQ9Y294 (Uniprot-TrEMBL)
ATM ProteinQ13315 (Uniprot-TrEMBL)
ATM dimer:KAT5ComplexR-HSA-5682037 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
Ac-CoAMetaboliteCHEBI:15351 (ChEBI)
Ac-K3016-ATM ProteinQ13315 (Uniprot-TrEMBL)
CABIN1 ProteinQ9Y6J0 (Uniprot-TrEMBL)
CABIN1ProteinQ9Y6J0 (Uniprot-TrEMBL)
CCNA1 ProteinP78396 (Uniprot-TrEMBL)
CCNA2 ProteinP20248 (Uniprot-TrEMBL)
CCNE1 ProteinP24864 (Uniprot-TrEMBL)
CCNE2 ProteinO96020 (Uniprot-TrEMBL)
CDK2 ProteinP24941 (Uniprot-TrEMBL)
CDKN1A Gene ProteinENSG00000124762 (Ensembl)
CDKN1A GeneGeneProductENSG00000124762 (Ensembl)
CDKN1A ProteinP38936 (Uniprot-TrEMBL)
CDKN1AProteinP38936 (Uniprot-TrEMBL)
CDKN1B ProteinP46527 (Uniprot-TrEMBL)
Cell Cycle CheckpointsPathwayR-HSA-69620 (Reactome) A hallmark of the human cell cycle in normal somatic cells is its precision. This remarkable fidelity is achieved by a number of signal transduction pathways, known as checkpoints, which monitor cell cycle progression ensuring an interdependency of S-phase and mitosis, the integrity of the genome and the fidelity of chromosome segregation.

Checkpoints are layers of control that act to delay CDK activation when defects in the division program occur. As the CDKs functioning at different points in the cell cycle are regulated by different means, the various checkpoints differ in the biochemical mechanisms by which they elicit their effect. However, all checkpoints share a common hierarchy of a sensor, signal transducers, and effectors that interact with the CDKs.

The stability of the genome in somatic cells contrasts to the almost universal genomic instability of tumor cells. There are a number of documented genetic lesions in checkpoint genes, or in cell cycle genes themselves, which result either directly in cancer or in a predisposition to certain cancer types. Indeed, restraint over cell cycle progression and failure to monitor genome integrity are likely prerequisites for the molecular evolution required for the development of a tumor. Perhaps most notable amongst these is the p53 tumor suppressor gene, which is mutated in >50% of human tumors. Thus, the importance of the checkpoint pathways to human biology is clear.

CoA-SHMetaboliteCHEBI:15346 (ChEBI)
Cyclin

A:Cdk2:p21/p27

complex		ComplexR-HSA-187926 (Reactome)
Cyclin

E:Cdk2:p21/p27

complex		ComplexR-HSA-68376 (Reactome)
Cyclin A:Cdk2 complexComplexR-HSA-141608 (Reactome)
Cyclin E:Cdk2 complexesComplexR-HSA-68374 (Reactome)
DNA DSBs:MRN:Ac-K3016-ATM dimer:KAT5ComplexR-HSA-5682035 (Reactome)
DNA DSBs:MRN:p-S1981,Ac-K3016-ATM:KAT5ComplexR-HSA-5682055 (Reactome)
DNA DSBs:MRN:ATM dimer:KAT5ComplexR-HSA-3785779 (Reactome)
DNA DSBs:MRNComplexR-HSA-3785763 (Reactome)
DNA Double Strand Break ResponsePathwayR-HSA-5693606 (Reactome) DNA double strand break (DSB) response involves sensing of DNA DSBs by the MRN complex which triggers ATM activation. ATM phosphorylates a number of proteins involved in DNA damage checkpoint signaling, as well as proteins directly involved in the repair of DNA DSBs. For a recent review, please refer to Ciccia and Elledge, 2010.
DNA R-NUL-29428 (Reactome)
DNA double-strand break endsR-NUL-75165 (Reactome)
DNA double-strand break ends R-NUL-75165 (Reactome)
DSB inducing agentsComplexR-HSA-R-ALL-6783909 (Reactome)
EP400 ProteinQ96L91 (Uniprot-TrEMBL)
EP400:p-S15-TP53

Tetramer:CDKN1A

Gene		ComplexR-HSA-4647605 (Reactome)
EP400ProteinQ96L91 (Uniprot-TrEMBL)
Extended And

Processed Telomere End and Associated DNA Binding and Packaging Protein Complex Folded Into Higher Order

Structure		ComplexR-HSA-182751 (Reactome)
G-strand Chromosome end with two additional single strand repeats and a subterminal loop - Telomeric R-HSA-182791 (Reactome)
H1F0 ProteinP07305 (Uniprot-TrEMBL)
H2AFB1 ProteinP0C5Y9 (Uniprot-TrEMBL)
H2AFX ProteinP16104 (Uniprot-TrEMBL)
H2AFZ ProteinP0C0S5 (Uniprot-TrEMBL)
H2BFS ProteinP57053 (Uniprot-TrEMBL)
HIRA ProteinP54198 (Uniprot-TrEMBL)
HIRA:ASF1A:UBN1:CABIN1ComplexR-HSA-3878132 (Reactome)
HIRAProteinP54198 (Uniprot-TrEMBL)
HIST1H1A ProteinQ02539 (Uniprot-TrEMBL)
HIST1H1B ProteinP16401 (Uniprot-TrEMBL)
HIST1H1C ProteinP16403 (Uniprot-TrEMBL)
HIST1H1D ProteinP16402 (Uniprot-TrEMBL)
HIST1H1E ProteinP10412 (Uniprot-TrEMBL)
HIST1H2AB ProteinP04908 (Uniprot-TrEMBL)
HIST1H2AC ProteinQ93077 (Uniprot-TrEMBL)
HIST1H2AD ProteinP20671 (Uniprot-TrEMBL)
HIST1H2AJ ProteinQ99878 (Uniprot-TrEMBL)
HIST1H2BA ProteinQ96A08 (Uniprot-TrEMBL)
HIST1H2BB ProteinP33778 (Uniprot-TrEMBL)
HIST1H2BC ProteinP62807 (Uniprot-TrEMBL)
HIST1H2BD ProteinP58876 (Uniprot-TrEMBL)
HIST1H2BH ProteinQ93079 (Uniprot-TrEMBL)
HIST1H2BJ ProteinP06899 (Uniprot-TrEMBL)
HIST1H2BK ProteinO60814 (Uniprot-TrEMBL)
HIST1H2BL ProteinQ99880 (Uniprot-TrEMBL)
HIST1H2BM ProteinQ99879 (Uniprot-TrEMBL)
HIST1H2BN ProteinQ99877 (Uniprot-TrEMBL)
HIST1H2BO ProteinP23527 (Uniprot-TrEMBL)
HIST1H4 ProteinP62805 (Uniprot-TrEMBL)
HIST2H2AA3 ProteinQ6FI13 (Uniprot-TrEMBL)
HIST2H2AC ProteinQ16777 (Uniprot-TrEMBL)
HIST2H2BE ProteinQ16778 (Uniprot-TrEMBL)
HIST3H2BB ProteinQ8N257 (Uniprot-TrEMBL)
HIST3H3 ProteinQ16695 (Uniprot-TrEMBL)
HMGA1 ProteinP17096 (Uniprot-TrEMBL)
HMGA1ProteinP17096 (Uniprot-TrEMBL)
HMGA2 ProteinP52926 (Uniprot-TrEMBL)
HMGA2ProteinP52926 (Uniprot-TrEMBL)
Histone H1 bound chromatin DNAComplexR-HSA-211238 (Reactome)
Histone H1ComplexR-HSA-211243 (Reactome)
Intrinsic Pathway for ApoptosisPathwayR-HSA-109606 (Reactome) The intrinsic (Bcl-2 inhibitable or mitochondrial) pathway of apoptosis functions in response to various types of intracellular stress including growth factor withdrawal, DNA damage, unfolding stresses in the endoplasmic reticulum and death receptor stimulation. Following the reception of stress signals, proapoptotic BCL-2 family proteins are activated and subsequently interact with and inactivate antiapoptotic BCL-2 proteins. This interaction leads to the destabilization of the mitochondrial membrane and release of apoptotic factors. These factors induce the caspase proteolytic cascade, chromatin condensation, and DNA fragmentation, ultimately leading to cell death. The key players in the Intrinsic pathway are the Bcl-2 family of proteins that are critical death regulators residing immediately upstream of mitochondria. The Bcl-2 family consists of both anti- and proapoptotic members that possess conserved alpha-helices with sequence conservation clustered in BCL-2 Homology (BH) domains. Proapoptotic members are organized as follows:

1. "Multidomain" BAX family proteins such as BAX, BAK etc. that display sequence conservation in their BH1-3 regions. These proteins act downstream in mitochondrial disruption.

2. "BH3-only" proteins such as BID,BAD, NOXA, PUMA,BIM, and BMF have only the short BH3 motif. These act upstream in the pathway, detecting developmental death cues or intracellular damage. Anti-apoptotic members like Bcl-2, Bcl-XL and their relatives exhibit homology in all segments BH1-4. One of the critical functions of BCL-2/BCL-XL proteins is to maintain the integrity of the mitochondrial outer membrane.

KAT5 ProteinQ92993 (Uniprot-TrEMBL)
KAT5ProteinQ92993 (Uniprot-TrEMBL)
LMNB1ProteinP20700 (Uniprot-TrEMBL)
MRE11A ProteinP49959 (Uniprot-TrEMBL)
MRNComplexR-HSA-75164 (Reactome)
Mitotic G1-G1/S phasesPathwayR-HSA-453279 (Reactome)
NBN ProteinO60934 (Uniprot-TrEMBL)
Oncogene Induced SenescencePathwayR-HSA-2559585 (Reactome) Oncogene-induced senescence is triggered by high level of RAS/RAF/MAPK signaling that can be caused, for example, by oncogenic mutations in RAS or RAF proteins, or by oncogenic mutations in growth factor receptors, such as EGFR, that act upstream of RAS/RAF/MAPK cascade. Oncogene-induced senescence can also be triggered by high transcriptional activity of E2F1, E2F2 or E2F3 which can be caused, for example, by the loss-of-function of RB1 tumor suppressor.

Oncogenic signals trigger transcription of CDKN2A locus tumor suppressor genes: p16-INK4A and p14-ARF. p16-INK4A and p14-ARF share exons 2 and 3, but are expressed from different promoters and use different reading frames. Therefore, while their mRNAs are homologous and are both translationally inhibited by miR-24 microRNA (Lal et al. 2008, To et al. 2012), they share no similarity at the amino acid sequence level and perform distinct functions in the cell. p16-INK4A acts as the inhibitor of cyclin-dependent kinases CDK4 and CDK6 which phosphorylate and inhibit RB1 protein thereby promoting G1 to S transition and cell cycle progression (Serrano et al. 1993). Increased p16-INK4A level leads to hypophosphorylation of RB1, allowing RB1 to inhibit transcription of E2F1, E2F2 and E2F3-target genes that are needed for cell cycle progression, which results in cell cycle arrest in G1 phase. p14-ARF binds and destabilizes MDM2 ubiquitin ligase (Zhang et al. 1998), responsible for ubiquitination and degradation of TP53 (p53) tumor suppressor protein (Wu et al. 1993, Fuchs et al. 1998, Fang et al. 2000). Therefore, increased p14-ARF level leads to increased level of TP53 and increased expression of TP53 target genes, such as p21, which triggers p53-mediated cell cycle arrest and, depending on other factors, may also lead to p53-mediated apoptosis. CDKN2B locus, which encodes an inhibitor of CDK4 and CDK6, p15-INK4B, is located in the vicinity of CDKN2A locus, at the chromosome band 9p21. p15-INK4B, together with p16-INK4A, contributes to senescence of human T-lymphocytes (Erickson et al. 1998) and mouse fibroblasts (Malumbres et al. 2000). SMAD3, activated by TGF-beta-1 signaling, controls senescence in the mouse multistage carcinogenesis model through regulation of MYC and p15-INK4B gene expression (Vijayachandra et al. 2003). TGF-beta-induced p15-INK4B expression is also important for the senescence of hepatocellular carcinoma cell lines (Senturk et al. 2010).

MAP kinases MAPK1 (ERK2) and MAPK3 (ERK1), which are activated by RAS signaling, phosphorylate ETS1 and ETS2 transcription factors in the nucleus (Yang et al. 1996, Seidel et al. 2002, Foulds et al. 2004, Nelson et al. 2010). Phosphorylated ETS1 and ETS2 are able to bind RAS response elements (RREs) in the CDKN2A locus and stimulate p16-INK4A transcription (Ohtani et al. 2004). At the same time, activated ERKs (MAPK1 i.e. ERK2 and MAPK3 i.e. ERK1) phosphorylate ERF, the repressor of ETS2 transcription, which leads to translocation of ERF to the cytosol and increased transcription of ETS2 (Sgouras et al. 1995, Le Gallic et al. 2004). ETS2 can be sequestered and inhibited by binding to ID1, resulting in inhibition of p16-INK4A transcription (Ohtani et al. 2004).

Transcription of p14-ARF is stimulated by binding of E2F transcription factors (E2F1, E2F2 or E2F3) in complex with SP1 to p14-ARF promoter (Parisi et al. 2002).

Oncogenic RAS signaling affects mitochondrial metabolism through an unknown mechanism, leading to increased generation of reactive oxygen species (ROS), which triggers oxidative stress induced senescence pathway. In addition, increased rate of cell division that is one of the consequences of oncogenic signaling, leads to telomere shortening which acts as another senescence trigger.

Oxidative Stress Induced SenescencePathwayR-HSA-2559580 (Reactome) Oxidative stress, caused by increased concentration of reactive oxygen species (ROS) in the cell, can happen as a consequence of mitochondrial dysfunction induced by the oncogenic RAS (Moiseeva et al. 2009) or independent of oncogenic signaling. Prolonged exposure to interferon-beta (IFNB, IFN-beta) also results in ROS increase (Moiseeva et al. 2006). ROS oxidize thioredoxin (TXN), which causes TXN to dissociate from the N-terminus of MAP3K5 (ASK1), enabling MAP3K5 to become catalytically active (Saitoh et al. 1998). ROS also stimulate expression of Ste20 family kinases MINK1 (MINK) and TNIK through an unknown mechanism, and MINK1 and TNIK positively regulate MAP3K5 activation (Nicke et al. 2005).


MAP3K5 phosphorylates and activates MAP2K3 (MKK3) and MAP2K6 (MKK6) (Ichijo et al. 1997, Takekawa et al. 2005), which act as p38 MAPK kinases, as well as MAP2K4 (SEK1) (Ichijo et al. 1997, Matsuura et al. 2002), which, together with MAP2K7 (MKK7), acts as a JNK kinase.


MKK3 and MKK6 phosphorylate and activate p38 MAPK alpha (MAPK14) and beta (MAPK11) (Raingeaud et al. 1996), enabling p38 MAPKs to phosphorylate and activate MAPKAPK2 (MK2) and MAPKAPK3 (MK3) (Ben-Levy et al. 1995, Clifton et al. 1996, McLaughlin et al. 1996, Sithanandam et al. 1996, Meng et al. 2002, Lukas et al. 2004, White et al. 2007), as well as MAPKAPK5 (PRAK) (New et al. 1998 and 2003, Sun et al. 2007).


Phosphorylation of JNKs (MAPK8, MAPK9 and MAPK10) by MAP3K5-activated MAP2K4 (Deacon and Blank 1997, Fleming et al. 2000) allows JNKs to migrate to the nucleus (Mizukami et al. 1997) where they phosphorylate JUN. Phosphorylated JUN binds FOS phosphorylated by ERK1 or ERK2, downstream of activated RAS (Okazaki and Sagata 1995, Murphy et al. 2002), forming the activated protein 1 (AP-1) complex (FOS:JUN heterodimer) (Glover and Harrison 1995, Ainbinder et al. 1997).


Activation of p38 MAPKs and JNKs downstream of MAP3K5 (ASK1) ultimately converges on transcriptional regulation of CDKN2A locus. In dividing cells, nucleosomes bound to the CDKN2A locus are trimethylated on lysine residue 28 of histone H3 (HIST1H3A) by the Polycomb repressor complex 2 (PRC2), creating the H3K27Me3 (Me3K-28-HIST1H3A) mark (Bracken et al. 2007, Kotake et al. 2007). The expression of Polycomb constituents of PRC2 (Kuzmichev et al. 2002) - EZH2, EED and SUZ12 - and thereby formation of the PRC2, is positively regulated in growing cells by E2F1, E2F2 and E2F3 (Weinmann et al. 2001, Bracken et al. 2003). H3K27Me3 mark serves as a docking site for the Polycomb repressor complex 1 (PRC1) that contains BMI1 (PCGF4) and is therefore named PRC1.4, leading to the repression of transcription of p16-INK4A and p14-ARF from the CDKN2A locus, where PCR1.4 mediated repression of p14-ARF transcription in humans may be context dependent (Voncken et al. 2005, Dietrich et al. 2007, Agherbi et al. 2009, Gao et al. 2012). MAPKAPK2 and MAPKAPK3, activated downstream of the MAP3K5-p38 MAPK cascade, phosphorylate BMI1 of the PRC1.4 complex, leading to dissociation of PRC1.4 complex from the CDKN2A locus and upregulation of p14-ARF transcription (Voncken et al. 2005). AP-1 transcription factor, formed as a result of MAP3K5-JNK signaling, as well as RAS signaling, binds the promoter of KDM6B (JMJD3) gene and stimulates KDM6B expression. KDM6B is a histone demethylase that removes H3K27Me3 mark i.e. demethylates lysine K28 of HIST1H3A, thereby preventing PRC1.4 binding to the CDKN2A locus and allowing transcription of p16-INK4A (Agger et al. 2009, Barradas et al. 2009, Lin et al. 2012).


p16-INK4A inhibits phosphorylation-mediated inactivation of RB family members by CDK4 and CDK6, leading to cell cycle arrest (Serrano et al. 1993). p14-ARF inhibits MDM2-mediated degradation of TP53 (p53) (Zhang et al. 1998), which also contributes to cell cycle arrest in cells undergoing oxidative stress. In addition, phosphorylation of TP53 by MAPKAPK5 (PRAK) activated downstream of MAP3K5-p38 MAPK signaling, activates TP53 and contributes to cellular senescence (Sun et al. 2007).

POT1 ProteinQ9NUX5 (Uniprot-TrEMBL)
RAD50 ProteinQ92878 (Uniprot-TrEMBL)
RAF/MAP kinase cascadePathwayR-HSA-5673001 (Reactome) The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
RB1ProteinP06400 (Uniprot-TrEMBL)
ROS MetaboliteCHEBI:26523 (ChEBI)
ROSMetaboliteCHEBI:26523 (ChEBI)
SAHFComplexR-HSA-4647600 (Reactome)
Senescence-Associated Secretory Phenotype (SASP)PathwayR-HSA-2559582 (Reactome) The culture medium of senescent cells in enriched in secreted proteins when compared with the culture medium of quiescent i.e. presenescent cells and these secreted proteins constitute the so-called senescence-associated secretory phenotype (SASP), also known as the senescence messaging secretome (SMS). SASP components include inflammatory and immune-modulatory cytokines (e.g. IL6 and IL8), growth factors (e.g. IGFBPs), shed cell surface molecules (e.g. TNF receptors) and survival factors. While the SASP exhibits a wide ranging profile, it is not significantly affected by the type of senescence trigger (oncogenic signalling, oxidative stress or DNA damage) or the cell type (epithelial vs. mesenchymal) (Coppe et al. 2008). However, as both oxidative stress and oncogenic signaling induce DNA damage, the persistent DNA damage may be a deciding SASP initiator (Rodier et al. 2009). SASP components function in an autocrine manner, reinforcing the senescent phenotype (Kuilman et al. 2008, Acosta et al. 2008), and in the paracrine manner, where they may promote epithelial-to-mesenchymal transition (EMT) and malignancy in the nearby premalignant or malignant cells (Coppe et al. 2008). Interleukin-1-alpha (IL1A), a minor SASP component whose transcription is stimulated by the AP-1 (FOS:JUN) complex (Bailly et al. 1996), can cause paracrine senescence through IL1 and inflammasome signaling (Acosta et al. 2013).

Here, transcriptional regulatory processes that mediate the SASP are annotated. DNA damage triggers ATM-mediated activation of TP53, resulting in the increased level of CDKN1A (p21). CDKN1A-mediated inhibition of CDK2 prevents phosphorylation and inactivation of the Cdh1:APC/C complex, allowing it to ubiquitinate and target for degradation EHMT1 and EHMT2 histone methyltransferases. As EHMT1 and EHMT2 methylate and silence the promoters of IL6 and IL8 genes, degradation of these methyltransferases relieves the inhibition of IL6 and IL8 transcription (Takahashi et al. 2012). In addition, oncogenic RAS signaling activates the CEBPB (C/EBP-beta) transcription factor (Nakajima et al. 1993, Lee et al. 2010), which binds promoters of IL6 and IL8 genes and stimulates their transcription (Kuilman et al. 2008, Lee et al. 2010). CEBPB also stimulates the transcription of CDKN2B (p15-INK4B), reinforcing the cell cycle arrest (Kuilman et al. 2008). CEBPB transcription factor has three isoforms, due to three alternative translation start sites. The CEBPB-1 isoform (C/EBP-beta-1) seems to be exclusively involved in growth arrest and senescence, while the CEBPB-2 (C/EBP-beta-2) isoform may promote cellular proliferation (Atwood and Sealy 2010 and 2011). IL6 signaling stimulates the transcription of CEBPB (Niehof et al. 2001), creating a positive feedback loop (Kuilman et al. 2009, Lee et al. 2010). NF-kappa-B transcription factor is also activated in senescence (Chien et al. 2011) through IL1 signaling (Jimi et al. 1996, Hartupee et al. 2008, Orjalo et al. 2009). NF-kappa-B binds IL6 and IL8 promoters and cooperates with CEBPB transcription factor in the induction of IL6 and IL8 transcription (Matsusaka et al. 1993, Acosta et al. 2008). Besides IL6 and IL8, their receptors are also upregulated in senescence (Kuilman et al. 2008, Acosta et al. 2008) and IL6 and IL8 may be master regulators of the SASP.

IGFBP7 is also an SASP component that is upregulated in response to oncogenic RAS-RAF-MAPK signaling and oxidative stress, as its transcription is directly stimulated by the AP-1 (JUN:FOS) transcription factor. IGFBP7 negatively regulates RAS-RAF (BRAF)-MAPK signaling and is important for the establishment of senescence in melanocytes (Wajapeyee et al. 2008).

Please refer to Young and Narita 2009 for a recent review.

Shelterin complexComplexR-HSA-174898 (Reactome)
Shortened

telomere:MRN:ATM

dimer:KAT5		ComplexR-HSA-5682021 (Reactome)
Shortened telomere:MRN:Ac-K3016-ATM dimer:KAT5ComplexR-HSA-6792710 (Reactome)
Shortened telomere:MRNComplexR-HSA-5682022 (Reactome)
Shortened telomere R-NUL-3785706 (Reactome)
Shortened telomereR-NUL-3785706 (Reactome)
TERF1 ProteinP54274 (Uniprot-TrEMBL)
TERF2 ProteinQ15554 (Uniprot-TrEMBL)
TERF2IP ProteinQ9NYB0 (Uniprot-TrEMBL)
TINF2 ProteinQ9BSI4 (Uniprot-TrEMBL)
TP53 ProteinP04637 (Uniprot-TrEMBL)
TP53 TetramerComplexR-HSA-3209194 (Reactome)
UBN1 ProteinQ9NPG3 (Uniprot-TrEMBL)
UBN1ProteinQ9NPG3 (Uniprot-TrEMBL)
X-ray MetaboliteCHEBI:30212 (ChEBI)
alpha-particle MetaboliteCHEBI:30216 (ChEBI)
beta-particle MetaboliteCHEBI:10545 (ChEBI)
dsDNAR-HSA-5649637 (Reactome)
gamma-ray MetaboliteCHEBI:30212 (ChEBI)
ligated C-strand Okazaki fragment R-NUL-176395 (Reactome)
p-S15-TP53

Tetramer:CDKN1A

Gene		ComplexR-HSA-3786257 (Reactome)
p-S15-TP53 ProteinP04637 (Uniprot-TrEMBL)
p-S15-TP53 TetramerComplexR-HSA-349474 (Reactome)
p-S1981,Ac-K3016-ATM ProteinQ13315 (Uniprot-TrEMBL)
p-S1981,Ac-K3016-ATMProteinQ13315 (Uniprot-TrEMBL)
p16-INK4aProteinP42771 (Uniprot-TrEMBL)
p21/p27ComplexR-HSA-182558 (Reactome)
proton MetaboliteCHEBI:24636 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-5682026 (Reactome)
ADPArrowR-HSA-5693540 (Reactome)
ADPArrowR-HSA-5693609 (Reactome)
ASF1AR-HSA-3878123 (Reactome)
ATM dimer:KAT5R-HSA-5682018 (Reactome)
ATM dimer:KAT5R-HSA-5693612 (Reactome)
ATPR-HSA-5682026 (Reactome)
ATPR-HSA-5693540 (Reactome)
ATPR-HSA-5693609 (Reactome)
Ac-CoAR-HSA-5682044 (Reactome)
Ac-CoAR-HSA-6792712 (Reactome)
ArrowR-HSA-4647594 (Reactome)
CABIN1R-HSA-3878123 (Reactome)
CDKN1A GeneR-HSA-3786258 (Reactome)
CDKN1A GeneR-HSA-4647613 (Reactome)
CDKN1AArrowR-HSA-4647613 (Reactome)
CoA-SHArrowR-HSA-5682044 (Reactome)
CoA-SHArrowR-HSA-6792712 (Reactome)
Cyclin

A:Cdk2:p21/p27

complex		ArrowR-HSA-187934 (Reactome)
Cyclin

E:Cdk2:p21/p27

complex		ArrowR-HSA-69562 (Reactome)
Cyclin A:Cdk2 complexR-HSA-187934 (Reactome)
Cyclin E:Cdk2 complexesR-HSA-69562 (Reactome)
DNA DSBs:MRN:Ac-K3016-ATM dimer:KAT5ArrowR-HSA-5682044 (Reactome)
DNA DSBs:MRN:Ac-K3016-ATM dimer:KAT5R-HSA-5693540 (Reactome)
DNA DSBs:MRN:Ac-K3016-ATM dimer:KAT5mim-catalysisR-HSA-5693540 (Reactome)
DNA DSBs:MRN:p-S1981,Ac-K3016-ATM:KAT5ArrowR-HSA-5693540 (Reactome)
DNA DSBs:MRN:ATM dimer:KAT5ArrowR-HSA-5693612 (Reactome)
DNA DSBs:MRN:ATM dimer:KAT5R-HSA-5682044 (Reactome)
DNA DSBs:MRN:ATM dimer:KAT5mim-catalysisR-HSA-5682044 (Reactome)
DNA DSBs:MRNArrowR-HSA-3785768 (Reactome)
DNA DSBs:MRNR-HSA-5693612 (Reactome)
DNA double-strand break endsArrowR-HSA-3785704 (Reactome)
DNA double-strand break endsR-HSA-3785768 (Reactome)
DSB inducing agentsR-HSA-3785704 (Reactome)
EP400:p-S15-TP53

Tetramer:CDKN1A

Gene		ArrowR-HSA-4647593 (Reactome)
EP400:p-S15-TP53

Tetramer:CDKN1A

Gene		TBarR-HSA-4647613 (Reactome)
EP400R-HSA-4647593 (Reactome)
Extended And

Processed Telomere End and Associated DNA Binding and Packaging Protein Complex Folded Into Higher Order

Structure		R-HSA-3785711 (Reactome)
HIRA:ASF1A:UBN1:CABIN1ArrowR-HSA-3878123 (Reactome)
HIRA:ASF1A:UBN1:CABIN1R-HSA-4647594 (Reactome)
HIRAR-HSA-3878123 (Reactome)
HMGA1R-HSA-4647594 (Reactome)
HMGA2R-HSA-4647594 (Reactome)
Histone H1 bound chromatin DNAR-HSA-4647594 (Reactome)
Histone H1ArrowR-HSA-4647594 (Reactome)
KAT5ArrowR-HSA-5682026 (Reactome)
LMNB1TBarR-HSA-4647594 (Reactome)
MRNR-HSA-3785768 (Reactome)
MRNR-HSA-5682020 (Reactome)
R-HSA-187934 (Reactome) During G1, the activity of cyclin-dependent kinases (CDKs) is kept in check by the CDK inhibitors (CKIs) p27 and p21, thereby preventing premature entry into S phase (see Guardavaccaro and Pagano, 2006).
R-HSA-3785704 (Reactome) Reactive oxygen species (ROS) induce DNA double strand breaks (DSBs) (Yu and Anderson 1997) in cells undergoing oxidative stress. In addition to ROS, DSBs can also be directly generated by ionizing radiation. Agents that interfere with the progression of replication forks, such as topoisomerase poisons used in chemotherapy, induce DSBs indirectly (Curtin 2012).
R-HSA-3785711 (Reactome) In somatic cells where telomerase is not active, telomeric DNA shortens with each cell division (Harley et al. 1990, Hastie et al. 1990). This may be especially pronounced in cells undergoing replicative exhaustion due to oncogenic signaling-driven cell division. The shelterin complex, which protects telomeres from being recognized as double strand DNA breaks (reviewed by de Lange 2005), binds telomeric DNA through interaction of its subunits TREF1 (TRF1) and TREF2 (TRF2) with long TTAGGG repeat tracts (Smogorzewska et al. 2000). Telomere shortening due to replicative exhaustion results in a decreased number of TTAGGG repeats, which negatively impacts shelterin binding to telomeric DNA.
R-HSA-3785768 (Reactome) The MRN complex (MRE11A:RAD50:NBN) binds to DNA ends found at double strand breaks (DNA DSBs) (Lee and Paull 2005). In budding yeast, the Mre11:Rad50:Xrs2 complex, homologous to human MRN, rapidly localizes to DNA breaks (Shroff et al. 2004, Lisby et al. 2004).
R-HSA-3786258 (Reactome) TP53, activated by ATM-mediated phosphorylation on S15 (Karlseder et al. 1999) binds CDKN1A (p21) promoter (El-Deiry et al. 1993).
R-HSA-3878123 (Reactome) The evolutionarily conserved complex of HIRA, ASF1A, UBN1 and CABIN1 plays a key role in the formation of senescence-associated heterochromatin foci (SAHF) (Zhang et al. 2005, Banumathy et al. 2009, Rai et al. 2011). Components of this complex, along with other proteins involved in SAHF, accumulate in PML bodies of pre-senescent cells, and relocate to SAHF in senescent cells, with SAHF relocation depending on the functional RB1 and TP53 pathways (Zhang et al. 2005, Ye et al. 2007, Zhang et al. 2007). HIRA serves as a scaffold of HIRA:ASF1A:UBN1:CABIN1 complex, since three different HIRA protein domains interact with ASF1A, UBN1 and CABIN1 (Zhang et al. 2005, Banumathy et al. 2009, Rai et al. 2011). One of the functions of HIRA:ASF1A:UBN1:CABIN1 complex is to deposit histone H3.3 variant onto chromatin, which is dependent on the ASF1A-mediated binding of histone H3, and is involved in the modulation of gene expression in senescent cells (Zhang et al. 2007, Rai et al. 2011).
R-HSA-4647593 (Reactome) EP400 (p400) binds to a CDKN1A promoter region that overlaps with the distal TP53-binding site and can co-localize with TP53 on CDKN1A promoter (Chan et al. 2005).
R-HSA-4647594 (Reactome) Components of the evolutionarily conserved complex of HIRA, ASF1A, UBN1 and CABIN1 accumulate in PML bodies of pre-senescent cells, and relocate to SAHF (senescence-associated heterochromatic foci) in senescent cells, with SAHF relocation depending on the functional RB1 and TP53 pathways (Zhang et al. 2005, Ye et al. 2007, Zhang et al. 2007). The reorganization of heterochromatin into SAHFs is accompanied by reduction in the amount of total and chromatin-bound lamin B1 (LMNB1), and high levels of LMNB1 interfere with SAHF formation (Sadaie et al. 2013). High-mobility group A proteins, HMGA1 and HMGA2, are enriched on chromatin of senescent cells, predominantly localizing to SAHFs, and high HMGA1 and HMGA2 levels, in cooperation with p16-INK4A, promote SAHF formation and repression of E2F target genes in senescent cells. Overexpression of CDK4 and MDM2, which are frequently co-amplified with HMGA2 in cancer cells as a part of 12q13-15 chromosomal band amplification, bypasses HMGA2 and HMGA1 induced cell cycle arrest and SAHF formation (Narita et al. 2006). The accumulation of HMGA proteins on senescent cell chromatin and SAHF formation is accompanied by the loss of the linker histone H1, probably due to a posttranslational mechanism (Funayama et al. 2006). A chromatin remodeling protein EP400 (p400), which is able to bind CDKN1A (p21) promoter and inhibit TP53-mediated activation of CDKN1A transcription, negatively regulates SAHF formation (Chan et al. 2005).
R-HSA-4647613 (Reactome) CDKN1A (p21) is transcriptionally activated by TP53 (p53) after DNA damage (el-Deiry et al. 1993). EP400 (p400) binds to a CDKN1A promoter region that overlaps with the distal TP53-binding site and can co-localize with TP53 on CDKN1A promoter. The presence of EP400 results in the downregulation of CDKN1A transcription without affecting the phosphorylation of TP53 on serine S15 (Chan et al. 2005).
R-HSA-5682018 (Reactome) Activation of ATM kinase in response to shortened telomeres requires association of ATM dimers with the MRN complex bound to DNA ends. MRN subunit RAD50 is essential for ATM dimer binding (Lee and Paull 2005, Wu et al. 2007). Dissociation of the shelterin complex from telomeres activates ATM (Karlseder et al. 1999), consistent with a mutually exclusive binding of shelterin and MRN to telomeric DNA (Wu et al. 2007).
R-HSA-5682020 (Reactome) The MRN complex (MRE11:RAD50:NBS1 also known as MRE11A:RAD50:NBN) binds telomeric DNA, and MRN association with telomeric DNA is mutually exclusive with shelterin binding (Wu et al. 2007).
R-HSA-5682026 (Reactome) MRN bound to shortened telomeres promotes dissociation of ATM dimers to ATM monomers which is accompanied by ATM autophosphorylation on serine residue S1981. Dissociation of ATM dimers requires the ATP-dependent DNA-helicase activity of the MRN subunit RAD50 (Lee and Paull 2005, Wu et al. 2007).
R-HSA-5682044 (Reactome) The histone acetyltransferase Tip60 (KAT5), in addition to forming a histone acetyltransferase complex with NuA4, forms another complex with ATM dimers. The ATM dimer:KAT5 complex is formed in the absence of DNA damage, but the acetyltransferase activity of KAT5 is activated by double strand DNA breaks (DNA DSBs) (Sun et al. 2005). In response to DNA DSBs, the MRN complex targets KAT5 to chromatin, where KAT5 associates with histone H3 trimethylated on lysine 10 (commonly known as H3K9me3 mark). Besides the MRN complex, the ability of KAT5 to access H3K9me3 depends on the DNA damage-induced displacement of HP1beta (CBX1) from H3K9me3 (Ayoub et al. 2008). Binding to H3K9me3 activates the acetyltransferase activity of KAT5 (Sun et al. 2009). KAT5 acetylates ATM on lysine residue K3016 in the highly conserved C-terminal FATC domain of ATM. ATM acetylation is needed for the activation of ATM kinase activity in response to DNA damage (Sun et al. 2007).
R-HSA-5693540 (Reactome) MRN promotes dissociation of ATM dimers to ATM monomers which is accompanied by ATM trans-autophosphorylation on serine residue S1981 (Bakkenist et al. 2003, Du et al. 2014). ATM autophosphorylation at serine residues S367 and S1893 is also implicated in ATM activation (Kozlov et al. 2006). Dissociation of ATM dimers requires the ATP-dependent DNA-helicase activity of the MRN subunit RAD50 (Lee and Paull 2005). KAT5 (Tip60) mediated acetylation of ATM dimers at lysine K3016 is a prerequisite for ATM kinase activity (Sun et al. 2007). Upon the dissociation of ATM dimers induced by DNA double strand breaks (DSBs), a fraction of activated ATM is retained at DSB sites, co-localizing with the MRN complex (Andegeko et al. 2001, Uziel et al. 2003) at ionizing radiation-induced foci (IRIF). MRN facilitates the binding of a portion of ATM substrates to ATM (Lee and Paull 2004).

After the DNA double strand breaks (DSBs) are repaired, ATM is dephosphorylated by an unidentified PP2A phosphatase complex, leading to dimer reformation (Goodarzi et al. 2004).

R-HSA-5693609 (Reactome) In response to DNA double strand breaks, serine at position 15 of the TP53 (p53) tumor suppressor protein is rapidly phosphorylated by the ATM kinase. This serves to stabilize the p53 protein. A rise in the levels of the p53 protein induces the expression of p21 cyclin-dependent kinase inhibitor. This prevents the normal progression from G1 to S phase, thus providing a check on replication of damaged DNA (Banin et al. 1998, Canman et al. 1998, Khanna et al. 1998).
R-HSA-5693612 (Reactome) Activation of ATM kinase in response to DNA damage in the form of DNA double strand breaks (DSBs) requires association of ATM dimers with the MRN complex bound to DNA ends. MRN subunit RAD50 is essential for ATM dimer binding (Lee and Paull 2005, Wu et al. 2007). ATM dimer exists in a preformed complex with KAT5 (Tip60) histone acetyltransferase (Sun et al. 2005).
R-HSA-6792712 (Reactome) The histone acetyltransferase Tip60 (KAT5), in addition to forming a histone acetyltransferase complex with NuA4, forms another complex with ATM dimers. The ATM dimer:KAT5 complex is formed in the absence of DNA damage, but the acetyltransferase activity of KAT5 is activated by double strand DNA breaks (DNA DSBs) (Sun et al. 2005) and likely by shortened telomeres. In response to DNA DSBs or, likely, shortened telomers, the MRN complex targets KAT5 to chromatin, where KAT5 associates with histone H3 trimethylated on lysine 10 (commonly known as H3K9me3 mark). Besides the MRN complex, the ability of KAT5 to access H3K9me3 depends on the DNA damage-induced displacement of HP1beta (CBX1) from H3K9me3 (Ayoub et al. 2008). HP1beta is also displaced from unprotected telomeres (Koering et al. 2002). Binding to H3K9me3 activates the acetyltransferase activity of KAT5 (Sun et al. 2009). KAT5 acetylates ATM on lysine residue K3016 in the highly conserved C-terminal FATC domain of ATM. ATM acetylation is needed for the activation of ATM kinase activity in response to DNA damage (Sun et al. 2007) and likely to shortened telomeres.
R-HSA-69562 (Reactome) During G1, the activity of cyclin-dependent kinases (CDKs) is kept in check by the CDK inhibitors (CKIs) p27 and p21, thereby preventing premature entry into S phase (see Guardavaccaro and Pagano, 2006). The efficient recognition and ubiquitination of p27 by the SCF(Skp2) complex requires the formation of a trimeric complex containing p27 and cyclin E/A:Cdk2.
SAHFArrowR-HSA-4647594 (Reactome)
Shelterin complexArrowR-HSA-3785711 (Reactome)
Shortened

telomere:MRN:ATM

dimer:KAT5		ArrowR-HSA-5682018 (Reactome)
Shortened

telomere:MRN:ATM

dimer:KAT5		R-HSA-6792712 (Reactome)
Shortened

telomere:MRN:ATM

dimer:KAT5		mim-catalysisR-HSA-6792712 (Reactome)
Shortened telomere:MRN:Ac-K3016-ATM dimer:KAT5ArrowR-HSA-6792712 (Reactome)
Shortened telomere:MRN:Ac-K3016-ATM dimer:KAT5R-HSA-5682026 (Reactome)
Shortened telomere:MRN:Ac-K3016-ATM dimer:KAT5mim-catalysisR-HSA-5682026 (Reactome)
Shortened telomere:MRNArrowR-HSA-5682020 (Reactome)
Shortened telomere:MRNArrowR-HSA-5682026 (Reactome)
Shortened telomere:MRNR-HSA-5682018 (Reactome)
Shortened telomereArrowR-HSA-3785711 (Reactome)
Shortened telomereR-HSA-5682020 (Reactome)
TBarR-HSA-4647594 (Reactome)
TP53 TetramerR-HSA-5693609 (Reactome)
UBN1R-HSA-3878123 (Reactome)
dsDNAR-HSA-3785704 (Reactome)
p-S15-TP53

Tetramer:CDKN1A

Gene		ArrowR-HSA-3786258 (Reactome)
p-S15-TP53

Tetramer:CDKN1A

Gene		ArrowR-HSA-4647613 (Reactome)
p-S15-TP53

Tetramer:CDKN1A

Gene		R-HSA-4647593 (Reactome)
p-S15-TP53 TetramerArrowR-HSA-4647594 (Reactome)
p-S15-TP53 TetramerArrowR-HSA-5693609 (Reactome)
p-S15-TP53 TetramerR-HSA-3786258 (Reactome)
p-S1981,Ac-K3016-ATMArrowR-HSA-5682026 (Reactome)
p-S1981,Ac-K3016-ATMArrowR-HSA-5693540 (Reactome)
p-S1981,Ac-K3016-ATMmim-catalysisR-HSA-5693609 (Reactome)
p21/p27R-HSA-187934 (Reactome)
p21/p27R-HSA-69562 (Reactome)
p21/p27mim-catalysisR-HSA-187934 (Reactome)
p21/p27mim-catalysisR-HSA-69562 (Reactome)

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