Replication fork stability confers chemoresistance in BRCA-deficient cells

Arnab Ray Chaudhuri, Elsa Callen, Xia Ding, Ewa Gogola, Alexandra A. Duarte, Ji-Eun Lee, Nancy Wong, Vanessa Lafarga, Jennifer A. Calvo, Nicholas J. Panzarino, Sam John, Amanda Day, Anna Vidal Crespo, Binghui Shen, Linda M. Starnes, Julian R. de Ruiter, Jeremy A. Daniel, Panagiotis A. Konstantinopoulos, David Cortez, Sharon B. Cantor, Oscar Fernandez-Capetillo, Kai Ge, Jos Jonkers, Sven Rottenberg, Shyam K. Sharan and André Nussenzweig ()
Additional contact information
Arnab Ray Chaudhuri: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health
Elsa Callen: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health
Xia Ding: Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health
Ewa Gogola: The Netherlands Cancer Institute
Alexandra A. Duarte: The Netherlands Cancer Institute
Ji-Eun Lee: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Nancy Wong: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health
Vanessa Lafarga: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO)
Jennifer A. Calvo: Cell, and Cancer Biology, University of Massachusetts Medical School, UMASS Memorial Cancer Center
Nicholas J. Panzarino: Cell, and Cancer Biology, University of Massachusetts Medical School, UMASS Memorial Cancer Center
Sam John: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health
Amanda Day: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health
Anna Vidal Crespo: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health
Binghui Shen: Beckman Research Institute of City of Hope
Linda M. Starnes: The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
Julian R. de Ruiter: The Netherlands Cancer Institute
Jeremy A. Daniel: The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
Panagiotis A. Konstantinopoulos: Dana Farber Cancer Institute, Harvard Medical School
David Cortez: Vanderbilt University School of Medicine
Sharon B. Cantor: Cell, and Cancer Biology, University of Massachusetts Medical School, UMASS Memorial Cancer Center
Oscar Fernandez-Capetillo: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO)
Kai Ge: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Jos Jonkers: The Netherlands Cancer Institute
Sven Rottenberg: The Netherlands Cancer Institute
Shyam K. Sharan: Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health
André Nussenzweig: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health

Nature, 2016, vol. 535, issue 7612, 382-387

Abstract: Abstract Cells deficient in the Brca1 and Brca2 genes have reduced capacity to repair DNA double-strand breaks by homologous recombination and consequently are hypersensitive to DNA-damaging agents, including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein, PTIP, protects Brca1/2-deficient cells from DNA damage and rescues the lethality of Brca2-deficient embryonic stem cells. However, PTIP deficiency does not restore homologous recombination activity at double-strand breaks. Instead, its absence inhibits the recruitment of the MRE11 nuclease to stalled replication forks, which in turn protects nascent DNA strands from extensive degradation. More generally, acquisition of PARP inhibitors and cisplatin resistance is associated with replication fork protection in Brca2-deficient tumour cells that do not develop Brca2 reversion mutations. Disruption of multiple proteins, including PARP1 and CHD4, leads to the same end point of replication fork protection, highlighting the complexities by which tumour cells evade chemotherapeutic interventions and acquire drug resistance.

Date: 2016
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DOI: 10.1038/nature18325

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