microhomology

Microhomology refers to short, shared sequences of nucleotides that can be used to align and join DNA ends during repair and recombination. These sequences are typically a few base pairs long (often about 2 to 25 bp) and occur near breakpoints in the genome. Microhomology can guide certain DNA repair processes, most notably microhomology-mediated end joining.

In cells, microhomology-mediated end joining (MMEJ) is an alternative pathway to repair double-strand breaks when other pathways are unavailable or resection is active. After resection exposes 3' single-stranded overhangs, short microhomologous regions on opposing ends anneal. The non-homologous flanking DNA is deleted, and nucleases and polymerases fill in gaps before ligation. This pathway is error-prone and often leaves characteristic short homologous sequences at junctions, sometimes accompanied by small insertions or deletions. In many organisms, polymerase theta (Polθ) plays a central role in MMEJ, coordinating annealing, gap filling, and ligation, with other factors such as CtIP and MRE11 influencing the initial resection step.

Microhomology is also involved in related genomic rearrangement processes, including microhomology-mediated break-induced replication (MMBIR) and microhomology-mediated translocations. These mechanisms can generate complex rearrangements such as deletions, duplications, inversions, and templated insertions, contributing to genome instability in various contexts.

Biological and medical relevance: MMEJ provides an alternative repair pathway that is more active when homologous recombination is compromised, contributing to genome instability in cancer and congenital disorders. Because BRCA-deficient tumors rely on Polθ-mediated MMEJ, inhibitors of Polθ are being explored as targeted therapeutic strategies.