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. 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

doi:10.1038/s41467-022-34519-8

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. 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^*

^*Corresponding author for this work

Molecular Genetics

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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.

Original language	English
Article number	6722
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-34519-8
Publication status	Published - 7 Nov 2022

Bibliographical note

Acknowledgements:
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).

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Heijink, A. M., Stok, C., Porubsky, D., Manolika, E. M., de Kanter, J. K., Kok, Y. P., Everts, M., de Boer, H. R., Audrey, A., Bakker, F. J., Wierenga, E., Tijsterman, M., Guryev, V., Spierings, D. C. J., Knipscheer, P., van Boxtel, R., Ray Chaudhuri, A., Lansdorp, P. M., & van Vugt, M. A. T. M. (2022). Sister chromatid exchanges induced by perturbed replication can form independently of BRCA1, BRCA2 and RAD51. Nature Communications, 13(1), Article 6722. https://doi.org/10.1038/s41467-022-34519-8

@article{d6c7c664416f4847b8ef9a88ee59d84c,

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

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.",

author = "Heijink, {Anne Margriet} and Colin Stok and David Porubsky and Manolika, {Eleni Maria} and {de Kanter}, {Jurrian K.} and Kok, {Yannick P.} and Marieke Everts and {de Boer}, {H. Rudolf} and Anastasia Audrey and Bakker, {Femke J.} and Elles Wierenga and Marcel Tijsterman and Victor Guryev and Spierings, {Diana C.J.} and Puck Knipscheer and {van Boxtel}, Ruben and {Ray Chaudhuri}, Arnab and Lansdorp, {Peter M.} and {van Vugt}, {Marcel A.T.M.}",

note = "Acknowledgements: 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 {\textquoteleft}CancerGenomiCs{\textquoteright} to P.K.), the European Research Council (ERC-Consolidator grant #681572 {\textquoteleft}TENSION{\textquoteright} 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: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = nov,

day = "7",

doi = "10.1038/s41467-022-34519-8",

language = "English",

volume = "13",

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Heijink, AM, Stok, C, Porubsky, D, Manolika, EM, de Kanter, JK, Kok, YP, Everts, M, de Boer, HR, Audrey, A, Bakker, FJ, Wierenga, E, Tijsterman, M, Guryev, V, Spierings, DCJ, Knipscheer, P, van Boxtel, R, Ray Chaudhuri, A, Lansdorp, PM & van Vugt, MATM 2022, 'Sister chromatid exchanges induced by perturbed replication can form independently of BRCA1, BRCA2 and RAD51', Nature Communications, vol. 13, no. 1, 6722. https://doi.org/10.1038/s41467-022-34519-8

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 - Acknowledgements: 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 - 2022/11/7

Y1 - 2022/11/7

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.

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DO - 10.1038/s41467-022-34519-8

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JO - Nature Communications

JF - Nature Communications

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ER -

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

Abstract

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