HDR through MMEJ (alt-NHEJ) (Homo sapiens)

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3, 4, 9, 10, 12...15, 17, 183, 7, 8, 199, 12, 194, 6, 12, 15, 161, 102-4, 8, 9, 12...1, 4, 1017cytosolnucleoplasmMRE11A RAD50 RBBP8 dNTPExtendedmicrohomologous3'-ssDNAoverhangs-DSB:MRN:RBBP8Extended microhomologous 3'-ssDNA overhangs-DSB Annealedmicrohomologous3'-ssDNAoverhangs-DSB:MRN:RBBP8:PARP1,PARP2:FEN1:POLQFEN1 RBBP8 homotetramerLIG3 PARP1,PARP2 dimersRBBP8 POLQ homodimerNBN PAR-PARP2 MRE11A dNTPNAD+XRCC1 Annealed microhomologous 3'-ssDNA overhangs-DSB RAD50 RAD50 MRE11A microhomologous 3'-ssDNA overhangs-DSB MRE11A Extendedmicrohomologous3'-ssDNAoverhangs-flap-DSB:MRN:RBBP8:PARP1,PARP2:FEN1:POLQRAD50 RBBP8 NBN NBN RBBP8 POLQ RBBP8 NBN NBN Extendedmicrohomologous3'-ssDNAoverhangs-DSB:MRN:RBBP8:LIG3:XRCC1Extendedmicrohomologous3'-ssDNAoverhangs-flap-DSB:MRN:RBBP8:FEN1RBBP8 RAD50 DNA Double StrandBreak ResponseNBN XRCC1 POLQ H2OMRNNBN Extended microhomologous 3'-ssDNA overhangs-DSB MRE11A RAD50 RBBP8 Extended microhomologous 3'-ssDNA overhans-flap-DSB PARP1 NBN NBN MRE11A DNA double-strand break ends RAD50 DNA double-strand break ends Microhomologous3'-ssDNAoverhangs-DSB:MRN:RBBP8FEN1PAR-PARP1 RAD50 Extended microhomologous 3'-ssDNA overhans-flap-DSB H2OMRE11A FEN1 PARP2 LIG3 PARP2 RAD50 PPidsDNA with basesubstitutions andinter-MMEJ deletionFEN1 MRE11A LIG3:XRCC1DNA DSBs:MRNFlapRBBP8 POLQ PAR-PARP1,PAR-PARP2dimersPARP2 NAMDNA DSB:MRN:RBBP8MRE11A PARP1 PARP1 11132012175


Description

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).<p>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). View original pathway at:Reactome.</div>

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Bibliography

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  1. Della-Maria J, Zhou Y, Tsai MS, Kuhnlein J, Carney JP, Paull TT, Tomkinson AE.; ''Human Mre11/human Rad50/Nbs1 and DNA ligase IIIalpha/XRCC1 protein complexes act together in an alternative nonhomologous end joining pathway.''; PubMed Europe PMC Scholia
  2. Kent T, Chandramouly G, McDevitt SM, Ozdemir AY, Pomerantz RT.; ''Mechanism of microhomology-mediated end-joining promoted by human DNA polymerase θ.''; PubMed Europe PMC Scholia
  3. Liu Y, Beard WA, Shock DD, Prasad R, Hou EW, Wilson SH.; ''DNA polymerase beta and flap endonuclease 1 enzymatic specificities sustain DNA synthesis for long patch base excision repair.''; PubMed Europe PMC Scholia
  4. Liang L, Deng L, Chen Y, Li GC, Shao C, Tischfield JA.; ''Modulation of DNA end joining by nuclear proteins.''; PubMed Europe PMC Scholia
  5. Lee JH, Paull TT.; ''ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex.''; PubMed Europe PMC Scholia
  6. Sharma S, Javadekar SM, Pandey M, Srivastava M, Kumari R, Raghavan SC.; ''Homology and enzymatic requirements of microhomology-dependent alternative end joining.''; PubMed Europe PMC Scholia
  7. Yun MH, Hiom K.; ''CtIP-BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle.''; PubMed Europe PMC Scholia
  8. Klungland A, Lindahl T.; ''Second pathway for completion of human DNA base excision-repair: reconstitution with purified proteins and requirement for DNase IV (FEN1).''; PubMed Europe PMC Scholia
  9. Davies OR, Forment JV, Sun M, Belotserkovskaya R, Coates J, Galanty Y, Demir M, Morton CR, Rzechorzek NJ, Jackson SP, Pellegrini L.; ''CtIP tetramer assembly is required for DNA-end resection and repair.''; PubMed Europe PMC Scholia
  10. Ceccaldi R, Liu JC, Amunugama R, Hajdu I, Primack B, Petalcorin MI, O'Connor KW, Konstantinopoulos PA, Elledge SJ, Boulton SJ, Yusufzai T, D'Andrea AD.; ''Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair.''; PubMed Europe PMC Scholia
  11. Mateos-Gomez PA, Gong F, Nair N, Miller KM, Lazzerini-Denchi E, Sfeir A.; ''Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination.''; PubMed Europe PMC Scholia
  12. Ghezraoui H, Piganeau M, Renouf B, Renaud JB, Sallmyr A, Ruis B, Oh S, Tomkinson AE, Hendrickson EA, Giovannangeli C, Jasin M, Brunet E.; ''Chromosomal translocations in human cells are generated by canonical nonhomologous end-joining.''; PubMed Europe PMC Scholia
  13. Prasad R, Lavrik OI, Kim SJ, Kedar P, Yang XP, Vande Berg BJ, Wilson SH.; ''DNA polymerase beta -mediated long patch base excision repair. Poly(ADP-ribose)polymerase-1 stimulates strand displacement DNA synthesis.''; PubMed Europe PMC Scholia
  14. Kubota Y, Nash RA, Klungland A, Schär P, Barnes DE, Lindahl T.; ''Reconstitution of DNA base excision-repair with purified human proteins: interaction between DNA polymerase beta and the XRCC1 protein.''; PubMed Europe PMC Scholia
  15. Ciccia A, Elledge SJ.; ''The DNA damage response: making it safe to play with knives.''; PubMed Europe PMC Scholia
  16. Rahal EA, Henricksen LA, Li Y, Williams RS, Tainer JA, Dixon K.; ''ATM regulates Mre11-dependent DNA end-degradation and microhomology-mediated end joining.''; PubMed Europe PMC Scholia
  17. Cistulli C, Lavrik OI, Prasad R, Hou E, Wilson SH.; ''AP endonuclease and poly(ADP-ribose) polymerase-1 interact with the same base excision repair intermediate.''; PubMed Europe PMC Scholia
  18. Satoh MS, Poirier GG, Lindahl T.; ''Dual function for poly(ADP-ribose) synthesis in response to DNA strand breakage.''; PubMed Europe PMC Scholia
  19. Lavrik OI, Prasad R, Sobol RW, Horton JK, Ackerman EJ, Wilson SH.; ''Photoaffinity labeling of mouse fibroblast enzymes by a base excision repair intermediate. Evidence for the role of poly(ADP-ribose) polymerase-1 in DNA repair.''; PubMed Europe PMC Scholia
  20. Mansour WY, Rhein T, Dahm-Daphi J.; ''The alternative end-joining pathway for repair of DNA double-strand breaks requires PARP1 but is not dependent upon microhomologies.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114701view16:18, 25 January 2021ReactomeTeamReactome version 75
113146view11:21, 2 November 2020ReactomeTeamReactome version 74
112376view15:30, 9 October 2020ReactomeTeamReactome version 73
101279view11:16, 1 November 2018ReactomeTeamreactome version 66
100816view20:47, 31 October 2018ReactomeTeamreactome version 65
100357view19:22, 31 October 2018ReactomeTeamreactome version 64
99903view16:05, 31 October 2018ReactomeTeamreactome version 63
99459view14:38, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93812view13:38, 16 August 2017ReactomeTeamreactome version 61
93354view11:21, 9 August 2017ReactomeTeamreactome version 61
87462view14:09, 22 July 2016MkutmonOntology Term : 'DNA repair pathway' added !
86438view09:18, 11 July 2016ReactomeTeamreactome version 56
83460view12:28, 18 November 2015ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
Annealed

microhomologous 3'-ssDNA

overhangs-DSB:MRN:RBBP8:PARP1,PARP2:FEN1:POLQ		ComplexR-HSA-5687514 (Reactome)
Annealed microhomologous 3'-ssDNA overhangs-DSB R-NUL-5687490 (Reactome)
DNA DSB:MRN:RBBP8ComplexR-HSA-5687468 (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 double-strand break ends R-NUL-75165 (Reactome)
Extended

microhomologous 3'-ssDNA

overhangs-DSB:MRN:RBBP8:LIG3:XRCC1		ComplexR-HSA-5687677 (Reactome)
Extended

microhomologous 3'-ssDNA

overhangs-DSB:MRN:RBBP8		ComplexR-HSA-5687663 (Reactome)
Extended

microhomologous 3'-ssDNA

overhangs-flap-DSB:MRN:RBBP8:FEN1		ComplexR-HSA-5687655 (Reactome)
Extended

microhomologous 3'-ssDNA

overhangs-flap-DSB:MRN:RBBP8:PARP1,PARP2:FEN1:POLQ		ComplexR-HSA-5687643 (Reactome)
Extended microhomologous 3'-ssDNA overhangs-DSB R-NUL-5687667 (Reactome)
Extended microhomologous 3'-ssDNA overhans-flap-DSB R-NUL-5687642 (Reactome)
FEN1 ProteinP39748 (Uniprot-TrEMBL)
FEN1ProteinP39748 (Uniprot-TrEMBL)
FlapR-NUL-68454 (Reactome)
H2OMetaboliteCHEBI:15377 (ChEBI)
LIG3 ProteinP49916 (Uniprot-TrEMBL)
LIG3:XRCC1ComplexR-HSA-110338 (Reactome)
MRE11A ProteinP49959 (Uniprot-TrEMBL)
MRNComplexR-HSA-75164 (Reactome)
Microhomologous

3'-ssDNA

overhangs-DSB:MRN:RBBP8		ComplexR-HSA-5687460 (Reactome)
NAD+MetaboliteCHEBI:15846 (ChEBI)
NAMMetaboliteCHEBI:17154 (ChEBI)
NBN ProteinO60934 (Uniprot-TrEMBL)
PAR-PARP1 ProteinP09874 (Uniprot-TrEMBL)
PAR-PARP1,PAR-PARP2 dimersComplexR-HSA-5651709 (Reactome)
PAR-PARP2 ProteinQ9UGN5 (Uniprot-TrEMBL)
PARP1 ProteinP09874 (Uniprot-TrEMBL)
PARP1,PARP2 dimersComplexR-HSA-5649884 (Reactome)
PARP2 ProteinQ9UGN5 (Uniprot-TrEMBL)
POLQ ProteinO75417 (Uniprot-TrEMBL)
POLQ homodimerComplexR-HSA-5687515 (Reactome)
PPiMetaboliteCHEBI:29888 (ChEBI)
RAD50 ProteinQ92878 (Uniprot-TrEMBL)
RBBP8 ProteinQ99708 (Uniprot-TrEMBL)
RBBP8 homotetramerComplexR-HSA-5684097 (Reactome)
XRCC1 ProteinP18887 (Uniprot-TrEMBL)
dNTPMetaboliteCHEBI:16516 (ChEBI)
dsDNA with base

substitutions and

inter-MMEJ deletion		R-NUL-5687670 (Reactome)
microhomologous 3'-ssDNA overhangs-DSB R-NUL-5687461 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
Annealed

microhomologous 3'-ssDNA

overhangs-DSB:MRN:RBBP8:PARP1,PARP2:FEN1:POLQ		ArrowR-HSA-5687484 (Reactome)
Annealed

microhomologous 3'-ssDNA

overhangs-DSB:MRN:RBBP8:PARP1,PARP2:FEN1:POLQ		R-HSA-5687640 (Reactome)
Annealed

microhomologous 3'-ssDNA

overhangs-DSB:MRN:RBBP8:PARP1,PARP2:FEN1:POLQ		mim-catalysisR-HSA-5687640 (Reactome)
DNA DSB:MRN:RBBP8ArrowR-HSA-5687465 (Reactome)
DNA DSB:MRN:RBBP8R-HSA-5687464 (Reactome)
DNA DSB:MRN:RBBP8mim-catalysisR-HSA-5687464 (Reactome)
DNA DSBs:MRNR-HSA-5687465 (Reactome)
Extended

microhomologous 3'-ssDNA

overhangs-DSB:MRN:RBBP8:LIG3:XRCC1		ArrowR-HSA-5687673 (Reactome)
Extended

microhomologous 3'-ssDNA

overhangs-DSB:MRN:RBBP8:LIG3:XRCC1		R-HSA-5687675 (Reactome)
Extended

microhomologous 3'-ssDNA

overhangs-DSB:MRN:RBBP8:LIG3:XRCC1		mim-catalysisR-HSA-5687675 (Reactome)
Extended

microhomologous 3'-ssDNA

overhangs-DSB:MRN:RBBP8		ArrowR-HSA-5687664 (Reactome)
Extended

microhomologous 3'-ssDNA

overhangs-DSB:MRN:RBBP8		R-HSA-5687673 (Reactome)
Extended

microhomologous 3'-ssDNA

overhangs-flap-DSB:MRN:RBBP8:FEN1		ArrowR-HSA-5687653 (Reactome)
Extended

microhomologous 3'-ssDNA

overhangs-flap-DSB:MRN:RBBP8:FEN1		R-HSA-5687664 (Reactome)
Extended

microhomologous 3'-ssDNA

overhangs-flap-DSB:MRN:RBBP8:FEN1		mim-catalysisR-HSA-5687664 (Reactome)
Extended

microhomologous 3'-ssDNA

overhangs-flap-DSB:MRN:RBBP8:PARP1,PARP2:FEN1:POLQ		ArrowR-HSA-5687640 (Reactome)
Extended

microhomologous 3'-ssDNA

overhangs-flap-DSB:MRN:RBBP8:PARP1,PARP2:FEN1:POLQ		R-HSA-5687653 (Reactome)
Extended

microhomologous 3'-ssDNA

overhangs-flap-DSB:MRN:RBBP8:PARP1,PARP2:FEN1:POLQ		mim-catalysisR-HSA-5687653 (Reactome)
FEN1ArrowR-HSA-5687664 (Reactome)
FEN1R-HSA-5687484 (Reactome)
FlapArrowR-HSA-5687664 (Reactome)
H2OR-HSA-5687464 (Reactome)
H2OR-HSA-5687664 (Reactome)
LIG3:XRCC1ArrowR-HSA-5687675 (Reactome)
LIG3:XRCC1R-HSA-5687673 (Reactome)
MRNArrowR-HSA-5687675 (Reactome)
Microhomologous

3'-ssDNA

overhangs-DSB:MRN:RBBP8		ArrowR-HSA-5687464 (Reactome)
Microhomologous

3'-ssDNA

overhangs-DSB:MRN:RBBP8		R-HSA-5687484 (Reactome)
NAD+R-HSA-5687653 (Reactome)
NAMArrowR-HSA-5687653 (Reactome)
PAR-PARP1,PAR-PARP2 dimersArrowR-HSA-5687653 (Reactome)
PARP1,PARP2 dimersR-HSA-5687484 (Reactome)
POLQ homodimerArrowR-HSA-5687653 (Reactome)
POLQ homodimerR-HSA-5687484 (Reactome)
PPiArrowR-HSA-5687640 (Reactome)
R-HSA-5687464 (Reactome) The complex of MRN (MRE11A:RAD50:NBN) and RBBP8 (CtIP) performs a limited resection of DNA double strand breaks (DSBs) in the process of microhomology-mediated end joining (MMEJ) (Yun et al. 2009). ATM activation inhibits MMEJ-related resection of DNA DSBs by MRN, possibly through MRN phosphorylation (Rahal et al. 2010).
R-HSA-5687465 (Reactome) In G1 phase, RBBP8 (CtIP) homotetramer associates with the MRN complex (MRE11A:RAD50:NBN) at DNA double strand breaks (DSBs) but does not undergo CDK2-mediated phosphorylation and is therefore unable to recruit BRCA1 (Yun et al. 2009). The activation of ATM DNA damage checkpoint is not needed for microhomology-mediated end joining (MMEJ or alt-NHEJ) (Rahal et al. 2010). MMEJ can also be triggered at other stages of the cell cycle, besides G1, when the amount of DNA DSBs overwhelms high fidelity DNA repair machinery (Liang et al. 2005).
R-HSA-5687484 (Reactome) Flap endonuclease FEN1, DNA polymerase theta (POLQ) and PARP1 or PARP2 homo- or heterodimers are recruited to DNA double strand breaks (DSBs) resected by MRN and RBBP8 (CtIP) in the process of microhomology-mediated end joining (MMEJ). The mechanism of recruitment of FEN1, PARP1 (or PARP2) and POLQ, which are all necessary for MMEJ progression (Liang et al. 2005, Mansour et al. 2010, Sharma et al. 2015, Mateos-Gomez et al. 2015, Ceccaldi et al. 2015, Kent et al. 2015), is poorly defined. PARP1 (or PARP2) recognizes ssDNA. In the DNA polymerase beta (POLB)-dependent long patch base excision repair (BER), PARPs form ternary complexes with FEN1 and POLB (Prasad et al. 2001, Lavrik et al. 2001, Cistulli et al. 2004), and it is possible that a similar mechanism involving PARPs, FEN1 and POLQ operates in MMEJ. POLQ functions as a homodimer and facilitates annealing of two 3'-ssDNA overhangs through their microhomology regions. POLQ requires <20 nucleotide (nt) long resected overhangs (Kent et al. 2015). Microhomology regions are optimally 10-19 nt long (Sharma et al. 2015), and the annealing is facilitated if the microhomology region is GC-rich (Kent et al. 2015).
R-HSA-5687640 (Reactome) DNA polymerase theta (POLQ) extends annealed microhomologous 3'-ssDNA overhangs at DNA double strand breaks (DSBs), using opposing overhangs as templates. POLQ can perform strand displacement synthesis, extending the overhangs beyond ssDNA-dsDNA junction point, which leads to the formation of displaced strand flaps (Kent et al. 2015). PARP1 (or possibly PARP2) is necessary for the recruitment of POLQ to DNA DSBs. POLQ-mediated DNA synthesis during microhomology mediated end joining (MMEJ) (also known as alternative nonhomologous end joining or alt-NHEJ) counteracts homologous recombination repair (HRR) and promotes survival of cells with a compromised HR pathway (Mateos-Gomez et al. 2015). POLQ is error-prone and introduces single nucleotide substitutions during DNA synthesis. HRR-deficient epithelial ovarian cancers frequently overexpress POLQ, which correlates with an increased frequency of somatic point mutations in these tumors (Ceccaldi et al. 2015).
R-HSA-5687653 (Reactome) PARP inihibitors that block catalytic activity of PARP1 (or PARP2) bound to single-stranded DNA (ssDNA), including PARP1 and PARP2 autoPARylation (auto-polyADPribosylation), also inhibit microhomology-mediated end joining (MMEJ). Thus, the catalytic activity of PARP1 (or PARP2), related to autoPARylation or PARylation of other proteins at MMEJ site, is necessary for the progression of MMEJ (Mansour et al. 2010, Ceccaldi et al. 2015). By analogy with the DNA polymerase beta (POLB)-dependent long patch base excision repair (Satoh et al. 1994, Prasad et al. 2001), autoPARylated PARPs dissociate from the repair site, thereby coordinating the termination of strand displacement DNA synthesis and the cleavage of displaced strand flaps by FEN1.
R-HSA-5687664 (Reactome) DNA polymerase theta (POLQ) performs strand displacement DNA synthesis during microhomology-mediated end joining (MMEJ) (Kent et al. 2015), which is expected to result in the formation of displaced 5'-ssDNA flaps. FEN1, a 5'-flap endonuclease, is a necessary participant of MMEJ (Liang et al. 2005, Sharma et al. 2015). By analogy with base excision repair (Klungland and Lindahl 1997, Liu et al. 2005), FEN1 is thought to cleave the 5'-flaps generated by POLQ-mediated DNA strand displacement synthesis during MMEJ, thus enabling the subsequent ligation step.
R-HSA-5687673 (Reactome) The MRN complex recruits DNA ligase 3 (LIG3) bound to XRCC1 (LIG3:XRCC1) to microhomology-mediated end joining (MMEJ) sites through direct interactions of the MRN subunits RAD50 and NBN (NBS1) with LIG3 (Della-Maria et al. 2011).
R-HSA-5687675 (Reactome) The complex of DNA ligase 3 (LIG3) and XRCC1 is necessary for the completion of microhomology-mediated end joining (MMEJ), although DNA ligase 1 (LIG1) may also be involved (Sharma et al. 2015). LIG3:XRCC1 is recruited to MMEJ sites by the MRN complex and ligates single strand nicks that remain after reparative DNA synthesis by DNA polymerase theta (POLQ) at DNA double strand break (DSB) sites (Della-Maria et al. 2011). The annealing of microhomology regions between two 3'-ssDNA overhangs of resected DNA DSBs during MMEJ leads to deletion of the intervening DNA sequence and one of the microhomology regions in repaired double strand DNA (dsDNA) (Ghezraoui et al. 2014). In addition, as POLQ is error-prone, repaired DNA contains base substitutions (Ceccaldi et al. 2015). Similar to nonhomologous end joining (NHEJ), MMEJ (also known as alternative-NHEJ) can also produce translocations by joining unrelated DNA molecules (Ghezraoui et al. 2014).
RBBP8 homotetramerArrowR-HSA-5687675 (Reactome)
RBBP8 homotetramerR-HSA-5687465 (Reactome)
dNTPArrowR-HSA-5687464 (Reactome)
dNTPR-HSA-5687640 (Reactome)
dsDNA with base

substitutions and

inter-MMEJ deletion		ArrowR-HSA-5687675 (Reactome)

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