title: Replication fork stability confers chemoresistance in BRCA-deficient cells.
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.
authors.affiliation: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Arnab
authors.initials: A
authors.lastname: Ray Chaudhuri
authors.affiliation: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Elsa
authors.initials: E
authors.lastname: Callen
authors.affiliation: Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Ding
authors.affiliation: Division of Molecular Pathology and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Ewa
authors.initials: E
authors.lastname: Gogola
authors.affiliation: Division of Molecular Pathology and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Alexandra A
authors.initials: AA
authors.lastname: Duarte
authors.affiliation: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Wong
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Lafarga
authors.affiliation: Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, UMASS Memorial Cancer Center, Worcester, Massachusetts 01605, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Calvo
authors.affiliation: Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, UMASS Memorial Cancer Center, Worcester, Massachusetts 01605, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Panzarino
authors.affiliation: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: John
authors.affiliation: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Day
authors.affiliation: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Anna Vidal
authors.initials: AV
authors.lastname: Crespo
authors.affiliation: Department of Radiation Biology, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, California 91010, USA.
authors.forename: Binghui
authors.initials: B
authors.lastname: Shen
authors.affiliation: The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Starnes
authors.affiliation: Division of Molecular Pathology and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Julian R
authors.initials: JR
authors.lastname: de Ruiter
authors.affiliation: The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Daniel
authors.affiliation: Departments of Gynecologic Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Panagiotis A
authors.initials: PA
authors.lastname: Konstantinopoulos
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, Tennessee 37232, USA.
authors.forename: David
authors.initials: D
authors.lastname: Cortez
authors.affiliation: Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, UMASS Memorial Cancer Center, Worcester, Massachusetts 01605, USA.
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Cantor
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernandez-Capetillo
authors.affiliation: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Ge
authors.affiliation: Division of Molecular Pathology and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.affiliation: Division of Molecular Pathology and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.|Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012 Bern, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Rottenberg
authors.affiliation: Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, USA.
authors.forename: Shyam K
authors.initials: SK
authors.lastname: Sharan
authors.affiliation: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: André
authors.initials: A
authors.lastname: Nussenzweig
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D059765:Homologous Recombination; D000076228:MRE11 Homologue Protein; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C512689:Mre11a protein, mouse; D009687:Nuclear Proteins; C412792:Paxip1 protein, mouse; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D004247:DNA; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D000076228:MRE11 Homologue Protein; C509277:Mi-2beta protein, mouse; D004265:DNA Helicases; D045643:DNA Repair Enzymes; D002945:Cisplatin