Microhomology-mediated end joining

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, the foremost distinguishing property of MMEJ is the use of 5–25 base pair (bp) microhomologous sequences during the alignment of broken ends before joining, thereby resulting in deletions flanking the original break. Thus, MMEJ is frequently associated with chromosome abnormalities such as deletions, translocations, inversions and other complex rearrangements.

Two other well-known means of double-strand breakage repair are non-homologous end joining and homologous recombination. MMEJ is distinguished from the other repair mechanisms by its use of 5–25 base pair microhomologous sequences to align the broken strands before joining. MMEJ uses a Ku protein and DNA-PK independent repair mechanism, and repair occurs during the S-phase of the cell cycle, as opposed to the G0/G1 and early S-phases in NHEJ and late S to G2-phase in HR.

MMEJ works by ligating the mismatched hanging strands of DNA, removing overhanging nucleotides, and filling in the missing base pairs. When a break occurs, a homology of 5 - 25 complementary base pairs on both strands is identified and used as a basis for which to align the strands with mismatched ends. Once aligned, any overhanging bases (flaps) and mismatched bases on the strands are removed and any missing nucleotides are inserted. As this method's only way of identifying if the two strands are related is based on microhomology down/upstream from the site of breakage, it does not identify any missing base pairs which may have been lost during the break, and even removes nucleotides (flaps) in order to ligate the strand. MMEJ ligates the DNA strands without checking for consistency and causes deletions, since it removes base pairs (flaps) in order to align the two pieces.

MMEJ is an error-prone method of repair and results in deletion mutations in the genetic code, which may initiate the creation of oncogenes that could lead to the development of cancer. In most cases a cell uses MMEJ only when the NHEJ method is unavailable or unsuitable, due to the disadvantage posed by introducing deletions into the genetic code.

A biochemical assay system shows that at least 6 genes are required for microhomology-mediated end joining: FEN1, Ligase III, MRE11, NBS1, PARP1 and XRCC1. All six of these genes are up-regulated in one or more cancers.

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