RRC ID 65235
Author Kamp JA, van Schendel R, Dilweg IW, Tijsterman M.
Title BRCA1-associated structural variations are a consequence of polymerase theta-mediated end-joining.
Journal Nat Commun
Abstract Failure to preserve the integrity of the genome is a hallmark of cancer. Recent studies have revealed that loss of the capacity to repair DNA breaks via homologous recombination (HR) results in a mutational profile termed BRCAness. The enzymatic activity that repairs HR substrates in BRCA-deficient conditions to produce this profile is currently unknown. We here show that the mutational landscape of BRCA1 deficiency in C. elegans closely resembles that of BRCA1-deficient tumours. We identify polymerase theta-mediated end-joining (TMEJ) to be responsible: knocking out polq-1 suppresses the accumulation of deletions and tandem duplications in brc-1 and brd-1 animals. We find no additional back-up repair in HR and TMEJ compromised animals; non-homologous end-joining does not affect BRCAness. The notion that TMEJ acts as an alternative to HR, promoting the genome alteration of HR-deficient cells, supports the idea that polymerase theta is a promising therapeutic target for HR-deficient tumours.
Volume 11(1)
Pages 3615
Published 2020-7-17
DOI 10.1038/s41467-020-17455-3
PII 10.1038/s41467-020-17455-3
PMID 32680986
PMC PMC7368036
MeSH Animals Animals, Genetically Modified Caenorhabditis elegans / genetics* Caenorhabditis elegans Proteins / genetics* DNA End-Joining Repair* DNA Mutational Analysis DNA Polymerase theta DNA-Directed DNA Polymerase / genetics DNA-Directed DNA Polymerase / metabolism* Gene Knockout Techniques Mutation Tumor Suppressor Proteins / genetics* Ubiquitin-Protein Ligases / genetics*
Resource
C.elegans tm2026