MMEJ

Microhomology-mediated end joining (MMEJ) is a DNA double-strand break repair pathway that uses short, exposed microhomology sequences near the break to align the broken ends for joining. It is considered an alternative end-joining mechanism distinct from classical non-homologous end joining (NHEJ) and homologous recombination (HR). In many contexts it is referred to as theta-mediated end joining (TMEJ) due to the prominent role of DNA polymerase theta (Polθ).

Mechanism and steps are as follows: after limited resection of the DNA ends reveals single-stranded tails, short microhomologies (typically 2–25 base pairs) anneal to each other. Nonhomologous flaps are removed, gaps are filled by Polθ, and the ends are ligated, often by DNA ligase III in complex with XRCC1. The process frequently results in deletions of the sequences between the microhomologies and can produce templated insertions at the junctions.

MMEJ is generally more error-prone than NHEJ and HR. It tends to be favored when HR is compromised or when classical NHEJ is reduced, and it leaves characteristic junctions with microhomology signatures. The pathway is largely dependent on Polθ, and its activity contributes to genomic alterations such as deletions and rearrangements.

Biological and clinical significance is notable. MMEJ is present in eukaryotes and can act as a backup repair pathway, particularly in BRCA-deficient cells. Overexpression or reliance on POLQ has been observed in various cancers and is associated with genomic instability. Because of its synthetic lethality with HR defects, POLQ inhibitors are being explored as potential cancer therapies, aiming to exploit tumor-specific dependencies on MMEJ.