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.
Highlights
Failure to preserve the integrity of the genome is a hallmark of cancer
Treatment with PARP inhibitors, which results in increased numbers of doublestrand DNA breaks (DSBs), is clinically effective in carcinomas that are deficient in homologous recombination (HR)[2], the major error-free pathway that repairs DSBs by predominantly using the sister chromatid as a undamaged template for repair
Because error-free HR is impaired in BRCA1- and BRCA2deficient cells[15,16], it is likely that error-prone repair of HR substrates are causal for the mutations observed in these tumours
Summary
Recent studies have revealed that loss of the capacity to repair DNA breaks via homologous recombination (HR) results in a mutational profile termed BRCAness. Deletions are losses of genetic information that can result from error-prone repair of DSBs; when repair is guided by annealing of complementary nucleotides present at the break ends, the deletion product will have so-called micro-homology at the junction[14]. Polymerase theta is a logical candidate to produce the micro-homology-mediated deletions in BRCA-deficient cells. To test this hypothesis, we here investigate spontaneous mutagenesis in C. elegans defective for brc-1 (BRCA1 ortholog). We find that brc1-deficient animals accumulate mutations similar to BRCA1deficient tumours (micro-homology-mediated deletions, tandem duplications and base substitutions), and we causally implicate polymerase theta in the emergence of structural variations. Our data demonstrate that polymerase theta acts as an alternative to HR by repairing HR intermediates, protecting the integrity of the genome but with mutations as a consequence
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