Microhomology-mediated end joining

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Microhomology-mediated end joining (MMEJ), also known as alternative nonhomologous end-joining (Alt-NHEJ) is one of the pathways for repairing double-strand breaks in DNA. As reviewed by McVey and Lee,^[1] the foremost distinguishing property of MMEJ is the use of microhomologous sequences during the alignment of broken ends before joining, thereby resulting in deletions flanking the original break. MMEJ is frequently associated with chromosome abnormalities such as deletions, translocations, inversions and other complex rearrangements.

There are multiple pathways for repairing double strand breaks, mainly non-homologous end joining (NHEJ), homologous recombination (HR), and MMEJ. NHEJ directly joins both ends of the double strand break and is relatively accurate, although small (usually less than a few nucleotides) insertions or deletions sometimes occur. HR is highly accurate and uses the sister chromatid as a template for accurate repair of the DSB. MMEJ is distinguished from these other repair mechanisms by its use of microhomologous sequences to align the broken strands. This results in frequent deletions and occasionally insertions which are much larger than those produced by NHEJ ^{[citation needed]}. MMEJ is completely independent from classical NHEJ and does not rely on NHEJ core factors such as Ku protein, DNA-PK, or Ligase IV.^[2]

In MMEJ, repair of the DSB is initiated by end resection by the MRE nuclease, leaving single stranded overhangs.^[3] These single stranded overhangs anneal at microhomologies, which are short regions of complementarity, often 5–25 base pairs, between the two strands. A specialized form of MMEJ, called polymerase theta-mediated end-joining (TMEJ), is able to repair breaks using ≥1 bp of homology.^[4][5] The helicase domain of DNA polymerase theta possesses ATP-dependent single-strand annealing activity and may promote annealing of microhomologies.^[6] Following annealing, any overhanging bases (flaps) are removed by nucleases such as Fen1 and gaps are filled in by DNA polymerase theta.^[7] This gap-filling ability of polymerase theta helps to stabilize the annealing of ends with minimal complementarity. Besides microhomology footprints, polymerase theta's mutational signature also consists of (infrequent) templated inserts, which are thought to be the result of aborted template-dependent extension, followed by re-annealing at secondary homologous sequences.^[5]