Sister chromatid exchanges induced by perturbed replication can form independently of BRCA1, BRCA2 and RAD51

Anne Margriet Heijink, Colin Stok, David Porubsky, Eleni Maria Manolika, Jurrian K. Kanter, Yannick P. Kok, Marieke Everts, H. Rudolf Boer, Anastasia Audrey, Femke J. Bakker, Elles Wierenga, Marcel Tijsterman, Victor Guryev, Diana C. J. Spierings, Puck Knipscheer, Ruben Boxtel, Arnab Ray Chaudhuri, Peter M. Lansdorp () and Marcel A. T. M. Vugt ()
Additional contact information
Anne Margriet Heijink: University Medical Center Groningen, University of Groningen, the Netherlands
Colin Stok: University Medical Center Groningen, University of Groningen, the Netherlands
David Porubsky: University Medical Center Groningen, University of Groningen
Eleni Maria Manolika: Erasmus University Medical Center
Jurrian K. Kanter: Princess Máxima Center for Pediatric Oncology
Yannick P. Kok: University Medical Center Groningen, University of Groningen, the Netherlands
Marieke Everts: University Medical Center Groningen, University of Groningen, the Netherlands
H. Rudolf Boer: University Medical Center Groningen, University of Groningen, the Netherlands
Anastasia Audrey: University Medical Center Groningen, University of Groningen, the Netherlands
Femke J. Bakker: University Medical Center Groningen, University of Groningen, the Netherlands
Elles Wierenga: University Medical Center Groningen, University of Groningen, the Netherlands
Marcel Tijsterman: Leiden University Medical Center
Victor Guryev: University Medical Center Groningen, University of Groningen
Diana C. J. Spierings: University Medical Center Groningen, University of Groningen
Puck Knipscheer: Oncode Institute
Ruben Boxtel: Princess Máxima Center for Pediatric Oncology
Arnab Ray Chaudhuri: Erasmus University Medical Center
Peter M. Lansdorp: University Medical Center Groningen, University of Groningen
Marcel A. T. M. Vugt: University Medical Center Groningen, University of Groningen, the Netherlands

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Sister chromatid exchanges (SCEs) are products of joint DNA molecule resolution, and are considered to form through homologous recombination (HR). Indeed, SCE induction upon irradiation requires the canonical HR factors BRCA1, BRCA2 and RAD51. In contrast, replication-blocking agents, including PARP inhibitors, induce SCEs independently of BRCA1, BRCA2 and RAD51. PARP inhibitor-induced SCEs are enriched at difficult-to-replicate genomic regions, including common fragile sites (CFSs). PARP inhibitor-induced replication lesions are transmitted into mitosis, suggesting that SCEs can originate from mitotic processing of under-replicated DNA. Proteomics analysis reveals mitotic recruitment of DNA polymerase theta (POLQ) to synthetic DNA ends. POLQ inactivation results in reduced SCE numbers and severe chromosome fragmentation upon PARP inhibition in HR-deficient cells. Accordingly, analysis of CFSs in cancer genomes reveals frequent allelic deletions, flanked by signatures of POLQ-mediated repair. Combined, we show PARP inhibition generates under-replicated DNA, which is processed into SCEs during mitosis, independently of canonical HR factors.

Date: 2022
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DOI: 10.1038/s41467-022-34519-8

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