Sister chromatid exchanges induced by perturbed replication can form independently of BRCA1, BRCA2 and RAD51
Nature Communications, vol. 13, pp. 6722
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.
Authors 19
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Genetics, University Medical Center Groningen, University of Groningen, the Netherlands, 9713GZ, Groningen, the Netherlands
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, the Netherlands, 9713GZ, Groningen, the Netherlands
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University Medical Center Groningen · University of Groningen · Institute of Genetics and Cancer · MRC Human Genetics Unit · University of Edinburgh
Affiliation as printed
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, the Netherlands, 9713GZ, Groningen, the Netherlands
MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh. Crewe Road South, Edinburgh, EH4 2XU, Edinburgh, UK
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University Medical Center Groningen · University of Groningen · University of Washington
Affiliation as printed
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, 98195, USA
European Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, 9713GZ, Groningen, the Netherlands
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3000, CA, Rotterdam, the Netherlands
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Oncode Institute · Princess Máxima Center
Affiliation as printed
Oncode Institute, 3521 AL, Utrecht, the Netherlands
Princess Máxima Center for Pediatric Oncology, 3584, CS, Utrecht, the Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, the Netherlands, 9713GZ, Groningen, the Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, the Netherlands, 9713GZ, Groningen, the Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, the Netherlands, 9713GZ, Groningen, the Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, the Netherlands, 9713GZ, Groningen, the Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, the Netherlands, 9713GZ, Groningen, the Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, the Netherlands, 9713GZ, Groningen, the Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center, 2333 ZC, Leiden, the Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
European Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, 9713GZ, Groningen, the Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
European Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, 9713GZ, Groningen, the Netherlands
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Utrecht University · University Medical Center Utrecht · Oncode Institute · Hubrecht Institute for Developmental Biology and Stem Cell Research
Affiliation as printed
Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, the Netherlands
Oncode Institute, 3521 AL, Utrecht, the Netherlands
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Oncode Institute · Princess Máxima Center
Affiliation as printed
Oncode Institute, 3521 AL, Utrecht, the Netherlands
Princess Máxima Center for Pediatric Oncology, 3584, CS, Utrecht, the Netherlands
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3000, CA, Rotterdam, the Netherlands
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Peter M. Lansdorp corresponding
BC Cancer Agency · University Medical Center Groningen · University of British Columbia · University of Groningen
Affiliation as printed
Department of Medical Genetics, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada. plansdor@bccrc.ca
European Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, 9713GZ, Groningen, the Netherlands. plansdor@bccrc.ca
Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, V5Z 1L3, Canada. plansdor@bccrc.ca
Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, V5Z 1L3, Canada
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Marcel A.T.M. van Vugt corresponding
University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, the Netherlands, 9713GZ, Groningen, the Netherlands. m.vugt@umcg.nl
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, the Netherlands, 9713GZ, Groningen, the Netherlands
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