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Publication Abstract from PubMed

The double-strand break (DSB) repair pathway called microhomology-mediated end-joining (MMEJ) is thought to be dependent on DNA polymerase theta (Poltheta) and occur independently of nonhomologous end-joining (NHEJ) factors. An unresolved question is whether MMEJ is facilitated by a single Poltheta-mediated end-joining pathway or consists of additional undiscovered pathways. We find that human X-family Pollambda, which functions in NHEJ, additionally exhibits robust MMEJ activity like Poltheta. Pollambda promotes MMEJ in mammalian cells independently of essential NHEJ factors LIG4/XRCC4 and Poltheta, which reveals a distinct Pollambda-dependent MMEJ mechanism. X-ray crystallography employing in situ photo-induced DSB formation captured Pollambda in the act of stabilizing a microhomology-mediated DNA synapse with incoming nucleotide at 2.0 A resolution and reveals how Pollambda performs replication across a DNA synapse joined by minimal base-pairing. Last, we find that Pollambda is semisynthetic lethal with BRCA1 and BRCA2. Together, these studies indicate Pollambda MMEJ as a distinct DSB repair mechanism.

Pollambda promotes microhomology-mediated end-joining.,Chandramouly G, Jamsen J, Borisonnik N, Tyagi M, Calbert ML, Tredinnick T, Ozdemir AY, Kent T, Demidova EV, Arora S, Wilson SH, Pomerantz RT Nat Struct Mol Biol. 2023 Jan;30(1):107-114. doi: 10.1038/s41594-022-00895-4. , Epub 2022 Dec 19. PMID:36536104^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.