1. Sister chromatid exchanges induced by perturbed replication can form independently of BRCA1, BRCA2 and RAD51
- Author
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Anne Margriet Heijink, Colin Stok, David Porubsky, Eleni Maria Manolika, Jurrian K. de Kanter, Yannick P. Kok, Marieke Everts, H. Rudolf de Boer, Anastasia Audrey, Femke J. Bakker, Elles Wierenga, Marcel Tijsterman, Victor Guryev, Diana C. J. Spierings, Puck Knipscheer, Ruben van Boxtel, Arnab Ray Chaudhuri, Peter M. Lansdorp, Marcel A. T. M. van Vugt, Hubrecht Institute for Developmental Biology and Stem Cell Research, Molecular Genetics, Groningen Research Institute for Asthma and COPD (GRIAC), Stem Cell Aging Leukemia and Lymphoma (SALL), Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
- Subjects
Multidisciplinary ,SDG 3 - Good Health and Well-being ,Chromosome Fragile Sites ,Homologous Recombination/genetics ,General Physics and Astronomy ,Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ,General Chemistry ,DNA ,Poly(ADP-ribose) Polymerase Inhibitors ,Homologous Recombination ,Sister Chromatid Exchange ,General Biochemistry, Genetics and Molecular Biology - Abstract
Sister chromatid exchanges (SCEs) are considered to be products of homologous recombination repair. The authors show that SCEs can arise independently of homologous recombination due to processing of replication intermediates during mitosis.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.
- Published
- 2022