Send to

Choose Destination
Nature. 2016 Jul 21;535(7612):382-7. doi: 10.1038/nature18325.

Replication fork stability confers chemoresistance in BRCA-deficient cells.

Author information

Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, USA.
Division of Molecular Pathology and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, UMASS Memorial Cancer Center, Worcester, Massachusetts 01605, USA.
Department of Radiation Biology, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, California 91010, USA.
The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
Departments of Gynecologic Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, Tennessee 37232, USA.
Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012 Bern, Switzerland.


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.

[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms


Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center