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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).
HRR and SSA share the initial steps that involve ATM signaling, formation of the so-called ionizing radiation-induced foci (IRIF), extensive resection of DNA DSB ends and activation of ATR signaling. In homologous recombination, 3'-ssDNA overhangs anneal with complementary sister chromatid strands. In SSA, 3'-ssDNA overhangs anneal with each other through homologous direct repeats contained in each overhang, resulting in deletions of one of the repeats and the DNA sequence in between the repeats during DNA repair synthesis.
Contrary to HRR and SSA, which both involve annealing of long stretches of highly homologous DNA sequences, MMEJ entails annealing of short regions of two 3'-ssDNA overhangs (up to 20 nucleotides) and is therefore more promiscuous and more likely to join unrelated DNA molecules. The error rate of MMEJ is additionally increased by the low fidelity of the DNA polymerase theta (POLQ), which performs DNA repair synthesis in MMEJ.
For reviews of this topic, please refer to Khanna 2001, Thompson and Schild 2001, Thompson and Schild 2002, Thompson and Limoli 2003, Ciccia and Elledge 2010.