Alternative non-homologous end joining pathway (Alt-NHEJ)

The **Alternative non-homologous end joining pathway** (Alt-NHEJ, also known as microhomology-mediated end joining or MMEJ) is a DNA repair mechanism used to fix double-strand breaks (DSBs) when the canonical non-homologous end joining (c-NHEJ) or homologous recombination (HR) fail or are disabled. Unlike c-NHEJ, which directly ligates DNA ends, alt-NHEJ utilizes short regions of homology (microhomologies) to align and join DNA ends, frequently resulting in deletions or insertions at the repair junction. The core molecular machinery includes DNA polymerase theta (POLQ) and various nucleases and ligases, but does not depend on the Ku heterodimer or Ligase IV that are critical for c-NHEJ. Alt-NHEJ is error-prone and promotes genomic instability by facilitating chromosomal translocations and other aberrant rearrangements, making it a driver of mutagenesis, carcinogenesis, and therapeutic resistance in cancer. The pathway has emerged as a promising therapeutic target, particularly in HR-deficient tumors, where reliance on Alt-NHEJ creates vulnerabilities that can be exploited by POLQ or PARP inhibitors.

Other names

Alternative end joining (A-EJ)Backup non-homologous end joining (B-NHEJ)Microhomology-mediated end joining (MMEJ)

Inhibition of pathway components (such as POLQ inhibitors or PARP inhibitors) impairs error-prone DSB repair, synthetic lethality especially in HR-deficient tumors