Replication fork stability confers chemoresistance in BRCA-deficient cells
Top Cited Papers
Open Access
- 20 July 2016
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 535 (7612), 382-387
- https://doi.org/10.1038/nature18325
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.Keywords
This publication has 44 references indexed in Scilit:
- The Replication Checkpoint Prevents Two Types of Fork Collapse without Regulating Replisome StabilityMolecular Cell, 2015
- Sae2 promotes DNA damage resistance by removing the Mre11–Rad50–Xrs2 complex from DNA and attenuating Rad53 signalingProceedings of the National Academy of Sciences of the United States of America, 2015
- BRCA1 haploinsufficiency for replication stress suppression in primary cellsNature Communications, 2014
- Mechanisms of resistance to therapies targeting BRCA-mutant cancersNature Medicine, 2013
- 53BP1 Regulates DSB Repair Using Rif1 to Control 5′ End ResectionScience, 2013
- Rif1 Prevents Resection of DNA Breaks and Promotes Immunoglobulin Class SwitchingScience, 2013
- Double-Strand Break Repair-Independent Role for BRCA2 in Blocking Stalled Replication Fork Degradation by MRE11Cell, 2011
- 53BP1 Inhibits Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNA BreaksCell, 2010
- 53BP1 is required for class switch recombinationThe Journal of cell biology, 2004
- Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancerNature Genetics, 2001