Defects in BRCA1, BRCA2 and
other genes of the homology-dependent DNA repair (HR) pathway cause an elevated rate
of mutagenesis, eliciting specific mutation patterns including COSMIC signature SBS3.
Using genome sequencing of knock-out cell lines we show that Y family translesion
synthesis (TLS) polymerases contribute to the spontaneous generation of base substitution
and short insertion/deletion mutations in BRCA1 deficient
cells, and that TLS on DNA adducts is increased in BRCA1
and BRCA2 mutants. The inactivation of 53BP1
in BRCA1 mutant cells markedly reduces TLS-specific mutagenesis,
and rescues the deficiency of template switch–mediated gene conversions in the immunoglobulin
V locus of BRCA1 mutant chicken DT40 cells. 53BP1 also
promotes TLS in human cellular extracts in vitro. Our results show that HR deficiency–specific
mutagenesis is largely caused by TLS, and suggest a function for 53BP1 in regulating
the choice between TLS and error-free template switching in replicative DNA damage
bypass.
