TY - JOUR
T1 - Sister chromatid exchanges induced by perturbed replication can form independently of BRCA1, BRCA2 and RAD51
AU - Heijink, Anne Margriet
AU - Stok, Colin
AU - Porubsky, David
AU - Manolika, Eleni Maria
AU - de Kanter, Jurrian K.
AU - Kok, Yannick P.
AU - Everts, Marieke
AU - de Boer, H. Rudolf
AU - Audrey, Anastasia
AU - Bakker, Femke J.
AU - Wierenga, Elles
AU - Tijsterman, Marcel
AU - Guryev, Victor
AU - Spierings, Diana C.J.
AU - Knipscheer, Puck
AU - van Boxtel, Ruben
AU - Ray Chaudhuri, Arnab
AU - Lansdorp, Peter M.
AU - van Vugt, Marcel A.T.M.
N1 - Funding Information:
This work was supported by grants from the Netherlands Organization for Scientific Research (NWO-VIDI 917.13334 to M.A.T.M.v.V. and Gravitation program ‘CancerGenomiCs’ to P.K.), the European Research Council (ERC-Consolidator grant #681572 ‘TENSION’ to M.A.T.M.v.V.), ERIBA-UMCG funding to A.M.H., P.L. and M.A.T.M.v.V. We thank Jos Jonkers, Thijn Brummelkamp and Shunichi Takeda for sharing reagents. We thank members of the Medical Oncology Department and ERIBA for feedback on the manuscript.
Funding Information:
This work was supported by grants from the Netherlands Organization for Scientific Research (NWO-VIDI 917.13334 to M.A.T.M.v.V. and Gravitation program ‘CancerGenomiCs’ to P.K.), the European Research Council (ERC-Consolidator grant #681572 ‘TENSION’ to M.A.T.M.v.V.), ERIBA-UMCG funding to A.M.H., P.L. and M.A.T.M.v.V. We thank Jos Jonkers, Thijn Brummelkamp and Shunichi Takeda for sharing reagents. We thank members of the Medical Oncology Department and ERIBA for feedback on the manuscript.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-022-34519-8
DO - 10.1038/s41467-022-34519-8
M3 - Article
AN - SCOPUS:85141505135
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
M1 - 6722
ER -