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.
View original pathway at Reactome.
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DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4
DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4
DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:PIAS4
DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4
Homology directed repair (HDR) of replication-independent DNA double strand breaks (DSBs) via homologous recombination repair (HRR) or single strand annealing (SSA) requires the activation of ATM followed by ATM-mediated phosphorylation of DNA repair proteins. ATM coordinates the recruitment of DNA repair and signaling proteins to DSBs and formation of the so-called ionizing radiation induced foci (IRIF). While IRIFs include chromatin regions kilobases away from the actual DSB, this Reactome pathway represents simplified foci and shows events that happen at the very ends of the broken DNA.
For both HRR and SSA to occur, the ends of the DNA DSB must be processed (resected) to generate lengthy 3' ssDNA tails, and the resulting ssDNA coated with RPA complexes, triggering ATR activation and signaling.
After the resection step, BRCA2 and RAD51 trigger HRR, a very accurate process in which the 3'-ssDNA overhang invades a sister chromatid, base pairs with the complementary strand of the sister chromatid DNA duplex, creating a D-loop, and uses the complementary sister chromatid strand as a template for DNA repair synthesis that bridges the DSB.
The SSA is triggered when 3'-ssDNA overhangs created in the resection step contain highly homologous direct repeats. In a process involving RAD52, the direct repeats in each 3'-ssDNA overhang become annealed, the unannealed 3'-flaps excised, and structures then processed by DNA repair synthesis. SSA results in the loss of one of the annealed repeats and the DNA sequence between the two repeats. Therefore, SSA is error-prone and is probably used as a backup for HRR, with RAD52 loss-of-function mutations being synthetically lethal with mutations in HRR genes, such as BRCA2 (reviewed by Ciccia and Elledge 2010).
Homology directed repair (HDR) through microhomology-mediated end joining (MMEJ) is an error prone process also known as alternative nonhomologous end joining (alt-NHEJ), although it does not involve proteins that participate in the classical NHEJ. Contrary to the classical NHEJ and other HDR pathways, homologous recombination repair (HRR) and single strand annealing (SSA), MMEJ does not require ATM activation. In fact, ATM activation inhibits MMEJ. Therefore, MMEJ may be triggered when the amount of DNA double strand breaks (DSBs) overwhelms DNA repair machinery of higher fidelity or when cells are deficient in components of high fidelity DNA repair.
MMEJ is initiated by a limited resection of DNA DSB ends by the MRN complex (MRE11A:RAD50:NBN) and RBBP8 (CtIP), in the absence of CDK2-mediated RBBP8 phosphorylation and related BRCA1:BARD1 recruitment (Yun and Hiom 2009). Single strand DNA (ssDNA) at resected DNA DSB ends recruits PARP1 or PARP2 homo- or heterodimers, together with DNA polymerase theta (POLQ) and FEN1 5'-flap endonuclease. In a poorly studied sequence of events, POLQ promotes the annealing of two 3'-ssDNA overhangs through microhomologous regions that are optimally 10-19 nucleotides long. Using analogy with POLB-mediated long patch base excision repair (BER), it is plausible that PARP1 (or PARP2) dimers coordinate the extension of annealed 3'-ssDNA overhangs via POLQ-mediated strand displacement synthesis with FEN1-mediated cleavage of the resulting 5'-flaps (Liang et al. 2005, Mansour et al. 2011, Sharma et al. 2015, Kent et al. 2015, Ciccaldi et al. 2015, Mateos-Gomez et al. 2015). The MRN complex subsequently recruits DNA ligase 3 (LIG3) bound to XRCC1 (LIG3:XRCC1) to ligate the remaining single strand nicks (SSBs) at MMEJ sites (Della-Maria et al. 2011).
Similar to single strand annealing (SSA), MMEJ leads to deletion of one of the microhomology regions used for annealing and the DNA sequence in between two annealed microhomology regions. MMEJ, just like classical NHEJ, can result in genomic translocations (Ghezraoui et al. 2014). In addition, since POLQ is an error-prone DNA polymerase, MMEJ introduces frequent base substitutions (Ceccaldi et al. 2015).
The nonhomologous end joining (NHEJ) pathway is initiated in response to the formation of DNA double-strand breaks (DSBs) induced by DNA-damaging agents, such as ionizing radiation. DNA DSBs are recognized by the MRN complex (MRE11A:RAD50:NBN), leading to ATM activation and ATM-dependent recruitment of a number of DNA damage checkpoint and repair proteins to DNA DSB sites (Lee and Paull 2005). The ATM phosphorylated MRN complex, MDC1 and H2AFX-containing nucleosomes (gamma-H2AX) serve as scaffolds for the formation of nuclear foci known as ionizing radiation induced foci (IRIF) (Gatei et al. 2000, Paull et al. 2000, Stewart et al. 2003, Stucki et al. 2005). Ultimately, both BRCA1:BARD1 heterodimers and TP53BP1 (53BP1) are recruited to IRIF (Wang et al. 2007, Pei et al. 2011, Mallette et al. 2012), which is necessary for ATM-mediated CHEK2 activation (Wang et al. 2002, Wilson et al. 2008). In G1 cells, TP53BP1 promotes NHEJ by recruiting RIF1 and PAX1IP, which displaces BRCA1:BARD1 and associated proteins from the DNA DSB site and prevents resection of DNA DSBs needed for homologous recombination repair (HRR) (Escribano-Diaz et al. 2013, Zimmermann et al. 2013, Callen et al. 2013). TP53BP1 also plays an important role in ATM-mediated phosphorylation of DCLRE1C (ARTEMIS) (Riballo et al. 2004, Wang et al. 2014). Ku70:Ku80 heterodimer (also known as the Ku complex or XRCC5:XRCC6) binds DNA DSB ends, competing away the MRN complex and preventing MRN-mediated resection of DNA DSB ends (Walker et al. 2001, Sun et al. 2012). The catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs, PRKDC) is then recruited to DNA-bound Ku to form the DNA-PK holoenzyme. Two DNA-PK complexes, one at each side of the break, bring DNA DSB ends together, joining them in a synaptic complex (Gottlieb 1993, Yoo and Dynan 2000). DNA-PK complex recruits DCLRE1C (ARTEMIS) to DNA DSB ends (Ma et al. 2002). PRKDC-mediated phosphorylation of DCLRE1C, as well as PRKDC autophosphorylation, enables DCLRE1C to trim 3'- and 5'-overhangs at DNA DSBs, preparing them for ligation (Ma et al. 2002, Ma et al. 2005, Niewolik et al. 2006). The binding of inositol phosphate may additionally stimulate the catalytic activity of PRKDC (Hanakahi et al. 2000). Other factors, such as polynucleotide kinase (PNK), TDP1 or TDP2 may remove unligatable damaged nucleotides from 5'- and 3'-ends of the DSB, converting them to ligatable substrates (Inamdar et al. 2002, Gomez-Herreros et al. 2013). DNA ligase 4 (LIG4) in complex with XRCC4 (XRCC4:LIG4) is recruited to ligatable DNA DSB ends together with the XLF (NHEJ1) homodimer and DNA polymerases mu (POLM) and/or lambda (POLL) (McElhinny et al. 2000, Hsu et al. 2002, Malu et al. 2002, Ahnesorg et al. 2006, Mahajan et al. 2002, Lee et al. 2004, Fan and Wu 2004). After POLL and/or POLM fill 1- or 2-nucleotide long single strand gaps at aligned DNA DSB ends, XRCC4:LIG4 performs the ligation of broken DNA strands, thus completing NHEJ. The presence of NHEJ1 homodimer facilitates the ligation step, especially at mismatched DSB ends (Tsai et al. 2007). Depending on other types of DNA damage present at DNA DSBs, NHEJ can result in error-free products, produce dsDNA with microdeletions and/or mismatched bases, or result in translocations (reviewed by Povrik et al. 2012).
DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4
DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4
DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4
DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4
DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4
DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:PIAS4
DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:PIAS4
DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4
DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4
DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:KDM4A,B:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4
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).
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).
BRCA1 and BARD1 form a stable heterodimer through an interaction between sequences encompassing their N-terminal RING domains (Wu et al. 1996, Brzovic et al. 2001). In addition to the RING domains, BRCA1 and BARD1 both have tandem BRCT motifs at their C termini. The central region of BARD1 contains ankyrin repeats (Wu et al. 1996). Formation of BRCA1:BARD1 heterodimers is necessary for the repair of double strand DNA breaks by homologous recombination (Westermark et al. 2003, Laufer et al. 2007), BRCA1-mediated tumor suppression (Shakya et al. 2008) and normal development (McCarthy et al. 2003). Tumorigenic BRCA1 mutations that abolish the formation of BRCA1:BARD1 heterodimers have been reported (Wu et al. 1996, Brzovic et al. 2001).
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).
PIAS4, an E3 SUMO ligase, is recruited to DNA double strand breaks (DSBs) via an unknown mechanism that requires a DNA-binding SAP domain of PIAS4 (Galanty et al. 2009). HERC2, an E3 ubiquitin ligase and a PIAS4 target, is recruited to DNA DSBs probably through its interaction with ATM (Bekker-Jensen et al. 2010).
RNF8 is an E3 ubiquitin ligase that, through its FHA domain, binds MDC1 phosphorylated at T-Q-X-F (Thr-Gln-X-Phe) sites by ATM. The phosphorylation of at least four T-Q-X-F sites of MDC1 (T699, T719, T752, T765) increases RNF8 binding to MDC1 (Kolas et al. 2007). RNF8 functions as a homodimer formed by interactions of the RNF8 coiled-coil domains (Cambell et al. 2012).
ATM phosphorylates HERC2 on threonine residue T4827. This threonine residue may also be phosphorylated by ATR and DNA-PKcs (PRKDC) (Bekker-Jensen et al. 2010).
PIAS4 SUMOylates HERC2 at an unknown lysine residue with SUMO1. ATM activity is needed for PIAS4-mediated HERC2 SUMOylation and it is therefore plausible that the ATM-mediated phosphorylation of HERC2 precedes HERC2 SUMOylation. Once SUMOylated, the ZZ domain of HERC2 interacts with the attached SUMO1 group, probably leading to a conformational change that allows binding of phosphorylated HERC2 to RNF8 (Bekker-Jensen et al. 2010, Danielsen et al. 2012).
HERC2 facilitates binding of the E2 ubiquitin conjugase dimer UBE2N:UBE2V2 (UBC13:MMS2) to RNF8 at DNA double strand breaks (DSBs) (Kolas et al. 2007, Bekker-Jensen et al. 2010, Campbell et al. 2012).
RNF8 and RNF168 E3 ubiquitin ligases work in concert with the E2 ubiquitin ligase complex UBE2N:UBE2V2 (UBC13:MMS2) to polyubiquitinate histone H2AFX (H2AX) on lysine residues K14 and K16 (commonly labeled in literature as K13 and K15) via ubiquitin lysine K63-directed cross-linking (Mattiroli et al. 2012). The scenario best supported by experimental evidence is that RNF8 initiates ubiquitination of H2AFX, followed by RNF168 binding to and extending ubiquitin chains ligated by RNF8 (Huen et al. 2007, Mailand et al. 2007, Stewart et al. 2009, Doil et al. 2009, Campbell et al. 2012).
The recruitment of RNF168, an E3 ubiquitin ligase, to DNA double strand breaks (DSBs) is facilitated by the interaction of RNF168 with the UBE2N:UBE2V2 (UBC13:MMS2) complex, which serves as the E2 ubiquitin ligase for both RNF8 and RNF168. In addition, because the two RNF168 ubiquitin interaction motifs (UIMs) are needed for the accumulation of RNF168 at DSBs, the initial ubiquitination of H2AFX (H2AX) histones by RNF8 is likely involved in RNF168 recruitment to DSBs. Inactivating mutations in both RNF168 alleles are responsible for the RIDDLE (radiosensitivity, immunodeficiency, dysmorphic features and learning difficulties) syndrome (Stewart et al. 2009, Doil et al. 2009, Bekker-Jensen et al. 2010, Campbell et al. 2012, Mattiroli et al. 2012).
WHSC1 (MMSET) histone methyltransferase dimethylates histone H4 (HIST1H4A) on lysine residue K21 (commonly labeled in literature as K20), locally increasing the concentration of the H4K20Me2 mark. H4K20Me2 (Me2-K21-HIST1H4A) serves as a binding site for TP53BP1 (53BP1). The recruitment of WHSC1 to DNA double strand breaks (DSBs) is independent of RNF8 and RNF168, but the catalytic activity of all three proteins is necessary for binding and accumulation of TP53BP1 at DSBs (Pei et al. 2011).
The histone methyltransferase WHSC1 (MMSET) is recruited to DNA double strand breaks (DSBs) likely through its interaction with histones and activated ATM (Pei et al. 2011).
Activated ATM phosphorylates WHSC1 (MMSET) on serine residue S102 (Matsuoka et al. 2007). The BRCT domain of MDC1 binds phosphorylated WHSC1, which is necessary for retention of WHSC1 at DNA double strand break (DSB) sites (Pei et al. 2011).
Histone demethylases KDM4A (JMJD2A) and KDM4B (JMJD2B) bind H4K20Me2 (Me2-K21-HIST1H4A) with a higher affinity than TP53BP1 (53BP1), thereby blocking TP53BP1 recruitment to DNA double strand breaks (DSBs). Demethylation of HIST1H4A (histone H4) by KDM4A or KDM4B is not involved in the inhibition of TP53BP1 binding (Mallette et al. 2012).
RNF8 and RNF168 polyubiquitinate KDM4A and KDM4B via ubiquitin lysine K48 cross-linking, leading to dissociation of ubiquitinated KDM4A and KDM4B from H4K20Me2 (Me2-K21-HIST1H4A) and subsequent proteasome-mediated degradation of KDM4A and KDM4B (Mallette et al. 2012).
UIMC1 (RAP80) is recruited to DNA double strand breaks (DSBs) through the interaction of its UIM (ubiquitin interaction motif) region with H2AFX (H2AX) ubiquitinated by RNF8 and RNF168 (Huen et al. 2007, Wang and Elledge 2007, Kolas et al. 2007, Mailand et al. 2007). A simultaneous interaction with FAM175A (Abraxas) through the AIR (Abraxas-interaction region) domain of UIMC1 facilitates UIMC1 binding to DNA DSBs. The interaction between UIMC1 and FAM175A and their loading to DNA DSBs is independent of BRCA1 (Wang et al. 2007, Wang and Elledge 2007).
A DNA damage-independent phosphorylation of FAM175A (Abraxas) serine residue S406 creates a pS-X-X-F (phospho-Ser-X-X-Phe) motif that binds BRCT repeats of BRCA1. The BRCA1 cancer predisposing mutation M1775R (Met1775Arg) inhibits BRCA1 binding to FAM175A. FAM175A interaction with UIMC1 (RAP80) enables BRCA1 recruitment to DNA double strand breaks (DSBs) (Wang et al. 2007). In addition to BRCA1, FAM175A also interacts with BRCC3 (BRCC36) (Wang et al. 2007, Hu et al. 2011) and BABAM1 (MERIT40, NBA1) (Vikrant et al. 2014). BABAM1 simultaneously interacts with BRE (BRCC45) (Hu et al. 2011). Together, BRCA1, BARD1, UIMC1, FAM175A, BRCC36, BRE and BABAM1 form the so-called BRCA1-A complex at DNA DSBs (Wang et al. 2009).
PPP5C-mediated dephosphorylation of TP53BP1 serine residues S25 and S1778 contributes to dissociation of TP53BP1 from DNA doubles strand break (DSB) sites and termination of DSB repair (Kang et al. 2009).
Activated ATM hyper-phosphorylates TP53BP1 (53BP1) at multiple residues in response to DNA damage (Fernandez-Capetillo et al. 2002, Ward et al. 2003, Jowsey et al. 2007). Phosphorylation of TP53BP1 serine residues S25 and S1778 is important for the retention of TP53BP1 at DNA double strand break (DSB) sites (Kang et al. 2009).
CHEK2 (CHK2, Cds1) is recruited to DNA double strand breaks (DSBs) mainly through its interaction with TP53BP1 (53BP1) (Wang et al. 2002), but BRCA1 also contributes to CHEK2 recruitment (Wilson and Stern 2008).
ATM-mediated phosphorylation of CHEK2 (CHK2, Cds1) on threonine residue T68 promotes formation of transitional CHEK2 homodimers primarily through intermolecular interactions of FHA domains and phospho-T68 residues of two CHEK2 protomers (Cai et al. 2009).
Upon dimerization, p-T68-CHEK2 protomers trans-autophosphorylate on serine residue S379 (Lovly et al. 2008) and threonine residues T383 and T387 (Lee et al. 2001). Autophosphorylation leads to dissociation of CHEK2 dimers into active CHEK2 monomers (Cai et al. 2009).
Activated CHEK2 phosphorylates BRCA1 on serine residue S988 (Lee et al. 2000), but does not phosphorylate BARD1, the heterodimerization partner of BRCA1 (Kim et al. 2006).
Under basal conditions, histone H2AFX (H2AX) is phosphorylated on tyrosine residue Y142 by the WICH complex composed of BAZ1B (WSTF) and SMARCA5 (SNF2H) (Xiao et al. 2009).
EYA tyrosine protein phosphatases (EYA1, EYA2 and EYA3) play an important role in repair of DNA double strand breaks (DSBs) (Cook et al. 2009, Krishnan et al. 2009). The role of EYA4 in the context of DNA damage has not been examined but is plausible based on sequence similarity. EYA3 is phosphorylated by activated ATM on serine residue S266 (labeled as S219 by Cook et al. 2009) and this phosphorylation is important for the catalytic activity of EYA3 (Cook et al. 2009). Although EYA1, EYA2 and EYA4 possess several sites that match the ATM consensus SQ/TQ sequence, their phosphorylation by ATM has not been examined
In response to DNA damage, EYA tyrosine protein phosphatases (EYA1, EYA2, EYA3 and, by sequence similarity, EYA4) dephosphorylate tyrosine Y142 of H2AFX, which allows the progression of DNA repair (Cook et al. 2009, Krishnan et al. 2009). It is possible that different EYA proteins heterodimerize in different cell types - the existence of a functional EYA1:EYA3 heterodimer in human embryonic kidney 293 (HEK293) cells is likely (Cook et al. 2009).
MCPH1 recognizes and binds diphosphorylated H2AFX, but the exact biological role of this interaction has not been elucidated (Singh et al. 2012).
In the absence of sufficient EYA1-4 activity, APBB1 (FE65) binds diphosphorylated H2AFX and recruits MAPK8 (JNK1) to H2AFX. This triggers pro-apoptotic signaling and targets the affected cell for apoptosis instead of DNA repair (Cook et al. 2009).
KPNA2 facilitates the translocation of NBN (NBS1) to the nucleus, thereby making NBN available for the formation of MRN complexes in response to DNA double strand breaks (DSBs) (Tseng et al. 2005).
In the cytosol, NBN (NBS1) binds KPNA2, an importin alpha family member. The armadillo repeats of KPNA2 and a nuclear localization signal (NLS) of NBN are involved in the interaction (Tseng et al. 2005).
ATM, activated in response to DNA damage in the form of double strand breaks, phosphorylates ABL1 (c-ABL) on serine residue S456, resulting in the activation of kinase activity of ABL1 (Baskaran et al. 1997).
The function of MDC1 in recruiting and retaining DNA repair proteins at the sites of DNA damage (Xu and Stern 2003, Stewart et al. 2003) is promoted by the ATM-mediated phosphorylation of MDC1 (Liu et al. 2012). Phosphorylation of MDC1 (NFBD1) by ATM at threonine residue T4 stabilizes otherwise unstable MDC1 homodimers by enabling in trans interaction of MDC1 FHA domains with phosphorylated N-terminal threonine residues (Goldberg et al. 2003, Liu et al. 2012). ATM also phosphorylates MDC1 on at least four threonine residues that match the consensus RNF8-binding sequence T-Q-X-F: T699, T719, T752, T765 (Kolas et al. 2007). Binding of the ubiquitin ligase RNF8 to ATM phosphorylated MDC1 is necessary for the recruitment of TP53BP1 and BRCA1 to DNA double strand break (DSB) sites.
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).
ATM phosphorylates histone H2AFX (H2AX) on serine S139 within 1-3 minutes of double strand break (DSB) formation, producing gamma-H2AX (gamma-H2AFX) (Rogakou et al.1998, Burma et al. 2001). Basal phosphorylation of H2AFX on tyrosine residue Y142 contributes to successful S139 phosphorylation and results in a transient diphosphorylated H2AFX (Cook et al. 2009). Gamma-H2AFX localizes to a region of about 2 Mbp surrounding the site of the DSB (Rogakou et al.1998), playing an essential role in the stable recruitment of other repair proteins and formation of ionizing radiation-induced foci (IRIF) at DSB sites (Paull et al. 2000, Celeste et al. 2002, Celeste et al. 2003, Stewart et al., 2003). Recruitment of MDC1 to gamma-H2AFX may be important for the sustained phosphorylation of H2AFX at DSBs (Stewart et al. 2003).
ATM phosphorylates BRCA1 at serine residues S1387, S1423, S1524 and S1547 (Cortez et al. 1999, Gatei et al. 2000). At least a fraction of these sites and some additional BRCA1 SQ/TQ sites can also be phosphorylated by ATR (Tibbetts et al. 2000). ATM also phosphorylates BARD1, the heterodimerization partner of BRCA1, at threonine residues T714 and T734 (Kim et al. 2006).
RNF8- and RNF168-mediated removal of KDM4A and KDM4B from H4K20Me2 (Me2-K21-HIST1H4A) enables TP53BP1 (53BP1) recruitment to WHSC1-methylated histone H4K20Me2 at DNA double strand breaks (DSBs) (Pei et al. 2011, Mallette et al. 2012)
Recruitment of MDC1 to nuclear foci (IRIF - ionizing radiation induced foci) is mediated by phosphorylated H2AFX (gamma-H2AX, gamma-H2AFX). Once bound, MDC1 promotes sustained phosphorylation of H2AFX by enhancing the interaction between ATM and H2AFX. The BRCT domain of MDC1 binds gamma-H2AFX, while the FHA domain of MDC1 interacts with ATM. Thus, ATM, H2AFX and MDC1 form a positive feedback loop that amplifies downstream ATM signaling and phosphorylation of other ATM targets (Goldberg et al. 2003, Stewart et al. 2003, Stucki et al. 2005, Lou et al. 2006). MDC1 also binds NBN (NBS1) component of the MRN complex, serving as a molecular linker between the MRN complex and the ATM-phosphorylated H2AFX. Although the initial recruitment of the MRN complex to DNA double strand breaks (DSBs) and ATM-mediated phosphorylation of NBN do not depend on MDC1, MDC1 is necessary for the retention of the MRN complex at DSB sites (Lukas et al. 2004).
NSB1 (NBN) is a component of the MRN (MRE11:RAD50:NBN) complex which acts early in homologous recombination repair (HRR) during recognition and resection of double-strand breaks (DSBs). ATM-mediated phosphorylation of NBN at serine residue S343 is required for activation of the S-phase checkpoint in response to ionizing radiation (IR), ATM-dependent activation of CHK2 and cell survival after exposure to IR (Lim et al. 2000, Gatei et al. 2000, Lee and Paull 2004). The phosphorylation of NBN by ATM may be enhanced by the presence of BRCA1 (Foray et al. 2003).
H2AFX (also known as H2AX) is a variant of histone H2A and is present in a portion of nucleosomes. While H2AFX-containing nucleosomes (H2AFX-nucleosomes) are not specifically recruited to the sites of DNA double strand breaks (DSBs), ATM recognizes the carboxyl tails of H2AFX on H2AFX-nucleosomes in the vicinity of DSBs as a suitable phosphorylation substrate. The phosphorylated H2AFX (gamma-H2AX) plays a crucial role in the retention of DNA repair proteins at DSBs, manifested in the formation of ionizing radiation-induced foci (Paull et al. 2000, Celeste et al. 2002, Redon et al. 2002, Celeste et al. 2003, Fernandez-Capetillo et al. 2004).
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).
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).
Activated ATM phosphorylates CHEK2 (CHK2, Cds1) on threonine residue T68 (Matsuoka et al. 2000, Melchionna et al. 2000). The presence of BRCA1 and TP53BP1 positively regulates ATM-mediated phosphorylation of CHEK2 (Wang et al. 2002, Foray et al. 2003). ATM-mediated phosphorylation causes formation of CHEK2 dimers and dissociation of CHEK2 from chromatin (Li and Stern 2005).
MRE11 has both manganese dependent ssDNA 3'->5' exonuclease and endonuclease activities. MRE11 associates with RAD50, resulting in increased 3'-5' exonuclease activity (Dolganov et al. 1996, Paull and Gellert 1998).
Binding of BAP1 to the BRCA1:BARD1 heterodimer disrupts the BRCA1:BARD1 association and consequently inhibits its E3 ubiquitin ligase activity. Downregulation of BAP1 expression results in the hypersensitivity of cells to ionizing radiation and in retardation of S phase progression, suggesting that BAP1 coordinates the enzymatic activity of the BRCA1:BARD1 complex during DNA double strand break response and during cell cycle (Nishikawa et al. 2009). While BAP1 is a deubiquitinating enzyme and may deubiquitinate some BRCA1:BARD1 substrates, it does not deubiquitinate autoubiquitinated BRCA1 and BARD1 (Mallery et al. 2002, Nishikawa et al. 2009). A catalytically-inactive mutant of BAP1, BAP1 C91S, is still able to inhibit BRCA1:BARD1-mediated ubiquitination, implying that BAP1 primarily regulates the action of the BRCA1:BARD1 complex by disrupting it (Nishikawa et al. 2009).
In vivo, most BRCA1 and BARD1 polypeptides exist in the form of the BRCA1:BARD1 heterodimer. Although BRCA1 and BARD1 each harbor a RING domain (Miki et al. 1994; Wu et al. 1996), only the RING domain of BRCA1 is known to associate functionally with E2 ubiquitin conjugating enzymes (Brzovic et al. 2001). In vitro, BRCA1 alone exhibits a residual E3 ligase activity that is dramatically enhanced upon heterodimerization with BARD1 (Hashizume et al. 2001, Chen et al. 2002, Mallery et al. 2002, Wu-Baer et al. 2003, Xia et al. 2003). In addition to extensive auto-polyubiquitination on multiple unidentified lysine residues of both BRCA1 and BARD1, the heterodimer also mono- and/or poly-ubiquitinates a number of other substrates, including the H2A histones (Ohta et al. 2011, Kalb et al. 2014). Depending on the associated E2 conjugase, BRCA1:BARD1 can generate polyubiquitin chains of various linkages, including K6-linked ubiquitin polymers, that are not typically involved in proteasomal degradation (Wu-Baer et al. 2003, Nishikawa et al. 2004, Christensen et al. 2007). Autoubiquitination has been reported to increase the enzymatic activity of the BRCA1:BARD1 complex and may promote DNA damage response signaling (Mallery et al. 2002). In contrast, its E3 ligase activity can be suppressed by association with regulatory factors such as the BAP1 ubiquitin hydrolase (Nishikawa et al. 2009) or the UBXN1 ubiquitin-binding protein (Wu-Baer et al. 2010). The cancer-predisposing BRCA1 missense mutation C61G prevents binding to BARD1 and thereby impairs the ubiquitin ligase activity of BRCA1 (Wu et al. 1996, Ransburgh et al. 2010, Brzovic et al. 2001, Mallery et al. 2002, Wu-Baer et al. 2003). Studies in mouse cells have shown that the ubiquitin ligase activity of BRCA1 is not essential for its role in tumor suppression (Shakya et al. 2011) or double-strand DNA break repair by homologous recombination.
BAP1 binds to the BRCA1:BARD1 complex mainly through interaction with BARD1, although BRCA1 enhances the interaction. Amino acid residues 182-365 of BAP1 bind to the RING domain of BARD1, but outside of the BRCA1-binding site in the BARD1 RING domain (Nishikawa et al. 2009).
The UBXN1 polypeptide can bind to and suppress the E3 ligase activity of autoubiquitinated BRCA1/BARD1 heterodimers. UBXN1 recognizes autoubiquitinated heterodimers through a bipartite interaction in which its UBA domain binds the conjugated K6-linked polyubiquitin chains of BRCA1:BARD1 while its C-terminal region binds BRCA1:BARD1 in a ubiquitin-independent manner.
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DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:TP53BP1DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:BRCA1-A complexDNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:UIMC1:p-S406-FAM175ADNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complex:CHEK2DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complexDNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-5S,2T-BRCA1-A complexDNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1Homologous Recombination (HRR) or Single Strand
Annealing (SSA)For both HRR and SSA to occur, the ends of the DNA DSB must be processed (resected) to generate lengthy 3' ssDNA tails, and the resulting ssDNA coated with RPA complexes, triggering ATR activation and signaling.
After the resection step, BRCA2 and RAD51 trigger HRR, a very accurate process in which the 3'-ssDNA overhang invades a sister chromatid, base pairs with the complementary strand of the sister chromatid DNA duplex, creating a D-loop, and uses the complementary sister chromatid strand as a template for DNA repair synthesis that bridges the DSB.
The SSA is triggered when 3'-ssDNA overhangs created in the resection step contain highly homologous direct repeats. In a process involving RAD52, the direct repeats in each 3'-ssDNA overhang become annealed, the unannealed 3'-flaps excised, and structures then processed by DNA repair synthesis. SSA results in the loss of one of the annealed repeats and the DNA sequence between the two repeats. Therefore, SSA is error-prone and is probably used as a backup for HRR, with RAD52 loss-of-function mutations being synthetically lethal with mutations in HRR genes, such as BRCA2 (reviewed by Ciccia and Elledge 2010).
MMEJ is initiated by a limited resection of DNA DSB ends by the MRN complex (MRE11A:RAD50:NBN) and RBBP8 (CtIP), in the absence of CDK2-mediated RBBP8 phosphorylation and related BRCA1:BARD1 recruitment (Yun and Hiom 2009). Single strand DNA (ssDNA) at resected DNA DSB ends recruits PARP1 or PARP2 homo- or heterodimers, together with DNA polymerase theta (POLQ) and FEN1 5'-flap endonuclease. In a poorly studied sequence of events, POLQ promotes the annealing of two 3'-ssDNA overhangs through microhomologous regions that are optimally 10-19 nucleotides long. Using analogy with POLB-mediated long patch base excision repair (BER), it is plausible that PARP1 (or PARP2) dimers coordinate the extension of annealed 3'-ssDNA overhangs via POLQ-mediated strand displacement synthesis with FEN1-mediated cleavage of the resulting 5'-flaps (Liang et al. 2005, Mansour et al. 2011, Sharma et al. 2015, Kent et al. 2015, Ciccaldi et al. 2015, Mateos-Gomez et al. 2015). The MRN complex subsequently recruits DNA ligase 3 (LIG3) bound to XRCC1 (LIG3:XRCC1) to ligate the remaining single strand nicks (SSBs) at MMEJ sites (Della-Maria et al. 2011).
Similar to single strand annealing (SSA), MMEJ leads to deletion of one of the microhomology regions used for annealing and the DNA sequence in between two annealed microhomology regions. MMEJ, just like classical NHEJ, can result in genomic translocations (Ghezraoui et al. 2014). In addition, since POLQ is an error-prone DNA polymerase, MMEJ introduces frequent base substitutions (Ceccaldi et al. 2015).
Annotated Interactions
DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:TP53BP1DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:TP53BP1DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:TP53BP1DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:TP53BP1DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:BRCA1-A complexDNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:BRCA1-A complexDNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:BRCA1-A complexDNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:UIMC1:p-S406-FAM175ADNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:UIMC1:p-S406-FAM175ADNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complex:CHEK2DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complex:CHEK2DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complex:CHEK2DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complexDNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complexDNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complexDNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complexDNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-5S,2T-BRCA1-A complexDNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1DNA
DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1MCPH1 recognizes and binds diphosphorylated H2AFX, but the exact biological role of this interaction has not been elucidated (Singh et al. 2012).
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).