microhomologymediated

Microhomology-mediated end joining (MMEJ) is a DNA double-strand break repair pathway that uses short, homologous DNA sequences, known as microhomologies, to align broken ends before joining. It is considered an alternative, error-prone form of end joining, typically acting as a backup when classical non-homologous end joining (NHEJ) or homologous recombination (HR) are inefficient or unavailable.

During MMEJ, nucleolytic resection exposes single-stranded overhangs containing microhomologies of roughly 2 to 20 base pairs. The matching microhomologies anneal, flaps are removed, and gap-filling synthesis precedes ligation. The repair is inherently mutagenic because it often deletes the sequence between the microhomologies and may introduce insertions at the junction.

Pol theta (POLQ) is a central enzymatic driver of MMEJ in many organisms, promoting annealing and synthesis at microhomology regions. Other factors, such as CtIP and MRE11, contribute to end resection, while ligation can involve DNA ligase III in complex with XRCC1.

MMEJ is relevant to cancer biology, particularly in tumors deficient in HR or BRCA genes, where reliance on MMEJ can drive genomic rearrangements. It also influences genome editing outcomes after programmable nucleases, by biasing repair toward microhomology-mediated junctions. Therapies targeting POLQ are being explored to treat such cancers.