DNA IR-double strand breaks and cellular response via ATM (Homo sapiens)

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62, 35351, 164, 304, 36016, 86, 175, 219, 224...207, 240, 276, 41454, 95, 208, 354, 40534, 229, 42971120, 296378, 42532897, 4031, 88, 146, 212, 243...273, 367145, 174, 355172, 337, 433235, 339, 40334428, 183, 302, 320, 39157306116383301, 346133, 307244356167, 361, 38237, 28915773, 16622248238, 273175193, 232149, 184177278, 4042731733283321753336516224, 34530862, 353195142, 28455, 142, 143255, 179, 252119, 305275, 368193, 383, 39472, 2929, 315, 397365, 389437376192, 3641531133342429532950136231163183053381362052, 67, 33238, 36611033841132, 189, 209, 280156303163, 37731533139, 53, 13829413309303DNA DSBsATM-TRAF6-cIAP1moduleNuA4complexIonizing Radiation (IR)Inhibition path22, 76, 79, 92, 105...23, 27, 59, 103, 147...SMC1AmRNA nonsense-mediateddecay (NMD)CohesinDCLRE1CBAK1SMC3MRE11ARAD50LATS1p73TP53BP1ApoptosisNBNBRCA1MCPH1The intra-S-phasecheckpoint mediatedarrest of cell cycleprogressionACTL6ACASP9MDM2UPF1BRCA2TP53DNA-PKEXO1TRAF6PARP1E2F1ATMMDC1RASSF1RAD51M-Phase ProgressionBAXTRIM28RAD17MCPH1KAT5PCNANFkB activationTERF2APAF1CDK5RAD52BLMOBFC2BSTK3ARF(CDKN2A)CHK1HSF1ATRCHK214, 130, 196, 242, 253...24, 345, 424108, 131, 176, 228, 32269, 185, 407, 409263, 313, 349, 428140, 236, 373191, 213, 301, 3462, 11, 374122, 125, 217, 38643, 47, 93, 336319, 332, 341, 351, 359...21, 160, 227, 330, 406134, 265, 329111, 121, 206, 43097, 235, 326, 339, 340, 40352, 91, 148, 257, 32117, 19, 31, 63, 124...18673, 115, 37045, 83, 214, 33366, 197, 226, 433395, 419, 42244, 200, 300, 325, 371...77, 129, 285100, 187, 255, 261, 392192, 248, 323, 364, 378...6, 151, 173, 288127, 151, 158, 28826, 65, 81, 135, 141...86, 279, 328190, 270, 317, 363, 379...114, 126, 251, 4184, 49, 239, 42041, 61, 75, 109, 169...220, 358, 419, 423, 4368636, 89, 274194, 215, 348, 350, 352...15, 283, 311, 421, 434356, 381, 402152, 182, 230, 234, 271...90, 101, 159144, 188, 210, 237, 245...5, 252, 324165, 359, 369, 416PATM30, 60, 68, 106, 161...PBID42, 117, 282RAD9A128, 362H2AX96, 107, 225, 287, 291...DNA Repair170, 171, 201, 298, 318PAPAF1CASP9CASP394, 99, 254, 272, 299...RNF878, 84, 338RIF1Cell CycleCheckpoint Activation154, 155, 1637, 85, 112, 132, 199G2/M-Phase Checkpoint87, 137, 221Damage ProcessingDNA Polymerasedelta tetramer70, 438118, 233, 400Member of the groupIntermediate paths not shownPath to processStimulation pathRelation to pathRelation to path(intermediate steps not shown)CDC25C58, 98, 431Translocation pathATMTRAF6Cell Survival168ABL110, 142, 180, 223ACTL6AKAT5211264MDM232ARF(CDKN2A)Cell cycle arrestat G1 & G2ARF-MD2McomplexATF240, 205, 393395, 419, 422181, 311175110110MRE11ARAD50NBNGammaH2AXMDC1249MRNcomplexYAP1828, 12, 123, 202FANCD213, 35, 74, 150, 198...3, 102, 139, 268, 269, 299...71, 78, 80, 84, 338FANCD1FANCD1BRCA246, 185, 4093156, 64, 104376


Description

Wide-ranging correlations are found between the initial physical features of radiation exposure and the possibility of biological consequences. These persist even with the chain of physical, chemical and biological processes that eliminate the majority of the early damage.

Ionizing radiations (IRs) generate hundreds of different simple chemical products in DNA as well multitudes of clustered combinations. The simple products, including single-strand breaks (SSBs), tend to correlate poorly with biological effectiveness. However, when IR produce double-strand breaks (DSBs) in DNA it comes a large rise in relative biological response to cellular damage. In general terms, IRs produce a wide variety of DNA lesions and DSBs are considered to be the major actor responsible for cell death. If unrepaired or improperly repaired, DSBs contribute to chromosomal aberrations, which may lead to human disorders including cancer. The accurate preservation of chromosome continuity in human cells during either DNA replication or repair is critical for preventing the conversion of normal cells to an oncogenic status.

The production of DSBs can be quantified by biochemical techniques, e.g., pulsed field gel electrophoresis (PFGE) and cell imaging, either globally or damage specific, through immunostaining of marker proteins or recruitment of fluorescent proteins to the DNA breaks.

In vertebrate cells, the elimination of DSBs with minimal nucleotide sequence change involves the spatiotemporal orchestration of an apparently endless number of proteins ranging, according to their action, from the nucleotide level to nucleosome organization and chromosome architecture. DSBs trigger a multitude of post-translational modifications that alter both, catalytic activities and the specificity of protein interactions including: phosphorylation, methylation, ubiquitylation, acetylation, and SUMOylation, followed by the turnaround of these changes as repair has been completed.

In mammalian cells, the formation of DSBs initiates a massive global cellular response, either checkpoint signaling and repair or cell death (apoptosis). A major role is that of the MRN (MRE11/RAD50/NBS1) complex binding to DSBs and facilitating the activation of ATM (Ataxia Telangiectasia Mutated) protein, a key PI3K (Phosphatidylinositol 3-kinase) related kinase in the DNA damage response (DDR). At the break site, ATM autophosphorylates, allowing its activation and the following phosphorylation of several substrates in the surrounding chromatin.

The following pathway diagrams the early events of the cellular response after DSBs by IR through the activation of ATM in human cells.

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History

View all...
CompareRevisionActionTimeUserComment
135238view22:34, 8 August 2024EweitzRemove obsolete, incorrect metadata
135237view22:33, 8 August 2024EweitzRefine complex label positions
135236view22:27, 8 August 2024EweitzRefine interaction curves
135235view22:24, 8 August 2024EweitzEconomize layout
135234view22:17, 8 August 2024EweitzRestore complex positions
135233view22:11, 8 August 2024EweitzRefine legend
135232view22:06, 8 August 2024EweitzEconomize layout
135231view22:02, 8 August 2024EweitzEconomize layout
118468view15:12, 27 May 2021Marvin M2removed empty ref
118466view15:10, 27 May 2021Marvin M2corrected author names
116540view12:10, 7 May 2021EweitzModified title
101991view19:16, 22 November 2018EgonwRemove
101834view13:03, 12 November 2018EgonwReplaced an old Uniprot data source with the new one.
95280view18:09, 29 November 2017AmanzoImprovements in conection lines.
95274view17:36, 28 November 2017AmanzoCorrection in line connections.
91367view20:47, 10 February 2017KhanspersModified title
91329view19:06, 31 January 2017Amanzo1 Datanode updated
91328view18:45, 31 January 2017Amanzo2 Datanodes updated
91327view18:13, 31 January 2017Amanzo5 Datanodes updated
91072view18:17, 30 December 2016AmanzoOntology Term : 'disease of cellular proliferation' added !
91071view18:15, 30 December 2016AmanzoOntology Term : 'altered programmed cell death pathway' added !
91070view18:14, 30 December 2016AmanzoOntology Term : 'pathway pertinent to DNA replication and repair, cell cycle, maintenance of genomic integrity, RNA and protein biosynthesis' added !
91069view18:13, 30 December 2016AmanzoOntology Term : 'altered double-strand DNA repair pathway' added !
91068view18:09, 30 December 2016AmanzoModified description
91065view17:29, 29 December 2016AmanzoNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ABL1ProteinP00519 (Uniprot-TrEMBL)
ACTL6AProteinO96019 (Uniprot-TrEMBL)
APAF1ProteinO14727 (Uniprot-TrEMBL)
ARF (CDKN2A)ProteinQ8N726 (Uniprot-TrEMBL)
ATF2GeneProductENSG00000115966 (Ensembl)
ATMGeneProductENSG00000149311 (Ensembl)
ATMProteinQ13315 (Uniprot-TrEMBL)
ATRProteinQ13535 (Uniprot-TrEMBL) From Pathway: SPIKE 00003
ApoptosisPathwayR-HSA-109581 (Reactome)
BAK1ProteinQ16611 (Uniprot-TrEMBL)
BAXProteinQ07812 (Uniprot-TrEMBL)
BIDProteinP55957 (Uniprot-TrEMBL)
BLMProteinP54132 (Uniprot-TrEMBL)
BRCA1ProteinP38398 (Uniprot-TrEMBL)
BRCA2ProteinP51587 (Uniprot-SwissProt)
BRCA2ProteinP51587 (Uniprot-TrEMBL)
CASP3ProteinP42574 (Uniprot-TrEMBL)
CASP9ProteinP55211 (Uniprot-TrEMBL)
CDC25CProteinP30307 (Uniprot-TrEMBL)
CDK5ProteinQ00535 (Uniprot-TrEMBL)
CHK1ProteinO14757 (Uniprot-TrEMBL)
CHK2ProteinO96017 (Uniprot-TrEMBL)
Cell Cycle Checkpoint ActivationPathwayWP1775 (WikiPathways)
Cell SurvivalPathway
Cell cycle arrest at G1 & G2Pathway
CohesinProtein
DCLRE1CProteinQ96SD1 (Uniprot-TrEMBL)
DNA Polymerase delta tetramerProteinP30261 (Uniprot-TrEMBL)
DNA RepairPathwayWP707 (WikiPathways)
DNA-PKProteinP78527 (Uniprot-TrEMBL)
Damage ProcessingPathway
E2F1ProteinQ01094 (Uniprot-TrEMBL)
EXO1ProteinQ9UQ84 (Uniprot-TrEMBL)
FANCD1ProteinP51587 (Uniprot-TrEMBL)
FANCD2ProteinQ9BXW9 (Uniprot-TrEMBL)
G2/M-Phase CheckpointPathwayR-HSA-69481 (Reactome)
Gamma H2AXProteinP16104 (Uniprot-TrEMBL)
H2AXProteinP16104 (Uniprot-TrEMBL)
HSF1ProteinQ00613 (Uniprot-TrEMBL)
KAT5ProteinQ92993 (Uniprot-TrEMBL) Q92993 is the catalytic subunit of the NuA4 histone acetyltransferase complex.
LATS1ProteinO95835 (Uniprot-TrEMBL)
M-Phase ProgressionPathwayhsa04110 (KEGG Pathway)
MCPH1ProteinQ8NEM0 (Uniprot-TrEMBL)
MDC1ProteinQ14676 (Uniprot-TrEMBL)
MDM2ProteinQ00987 (Uniprot-TrEMBL)
MRE11AProteinP49959 (Uniprot-TrEMBL)
NBNProteinO60934 (Uniprot-TrEMBL)
NFkB activationPathway
OBFC2BProteinQ9BQ15 (Uniprot-TrEMBL)
PARP1ProteinP09874 (Uniprot-TrEMBL)
PCNAProteinP12004 (Uniprot-TrEMBL)
RAD17ProteinO75943 (Uniprot-TrEMBL)
RAD50ProteinQ92878 (Uniprot-TrEMBL)
RAD51ProteinQ06609 (Uniprot-TrEMBL)
RAD52ProteinP43351 (Uniprot-TrEMBL)
RAD9AGeneProductENSG00000172613 (Ensembl)
RASSF1ProteinQ9NS23 (Uniprot-TrEMBL)
RIF1ProteinQ5UIP0 (Uniprot-TrEMBL)
RNF8ProteinO76064 (Uniprot-TrEMBL)
SMC1AProteinQ14683 (Uniprot-TrEMBL)
SMC3ProteinQ9UQE7 (Uniprot-TrEMBL)
STK3ProteinQ13188 (Uniprot-TrEMBL)
TERF2ProteinQ15554 (Uniprot-TrEMBL)
TP53BP1ProteinQ12888 (Uniprot-TrEMBL)
TP53ProteinP04637 (Uniprot-TrEMBL)
TRAF6ProteinQ9Y4K3 (Uniprot-TrEMBL)
TRIM28ProteinQ13263 (Uniprot-TrEMBL)
The intra-S-phase

checkpoint mediated arrest of cell cycle

progression		PathwayR-HSA-5693571 (Reactome)
UPF1ProteinQ92900 (Uniprot-TrEMBL)
YAP1ProteinP46937 (Uniprot-TrEMBL)
mRNA nonsense-mediated decay (NMD)Pathway
p73ProteinO15350 (Uniprot-TrEMBL)

Annotated Interactions

SourceTargetTypeDatabase referenceComment
ATMmim-stimulation00006 (SPIKE)
Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP3959"
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