BRCA1 deficiency specific base substitution mutagenesis is dependent on translesion synthesis and regulated by 53BP1

Dan Chen, Judit Z. Gervai, Ádám Póti, Eszter Németh, Zoltán Szeltner, Bernadett Szikriszt, Zsolt Gyüre, Judit Zámborszky, Marta Ceccon, Fabrizio d’Adda di Fagagna, Zoltan Szallasi, Andrea L. Richardson () and Dávid Szüts ()
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Dan Chen: Research Centre for Natural Sciences
Judit Z. Gervai: Research Centre for Natural Sciences
Ádám Póti: Research Centre for Natural Sciences
Eszter Németh: Research Centre for Natural Sciences
Zoltán Szeltner: Research Centre for Natural Sciences
Bernadett Szikriszt: Research Centre for Natural Sciences
Zsolt Gyüre: Research Centre for Natural Sciences
Judit Zámborszky: Research Centre for Natural Sciences
Marta Ceccon: IFOM Foundation-FIRC Institute of Molecular Oncology Foundation
Fabrizio d’Adda di Fagagna: IFOM Foundation-FIRC Institute of Molecular Oncology Foundation
Zoltan Szallasi: Boston Children’s Hospital and Harvard Medical School
Andrea L. Richardson: Johns Hopkins University School of Medicine
Dávid Szüts: Research Centre for Natural Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-021-27872-7

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