Replication Fork Stability Confers Chemoresistance in BRCA-deficient Cells

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Author
Chaudhuri, Arnab Ray
Callen, Elsa
Ding, Xia
Gogola, Ewa
Duarte, Alexandra A.
Lee, Ji-Eun
Wong, Nancy
Lafarga, Vanessa
Calvo, Jennifer A.
Panzarino, Nicholas J.
John, Sam
Day, Amanda
Crespo, Anna Vidal
Shen, Binghui
Starnes, Linda M.
de Ruiter, Julian R.
Daniel, Jeremy A.
Cortez, David
Cantor, Sharon B.
Fernandez-Capetillo, Oscar
Ge, Kai
Jonkers, Jos
Rottenberg, Sven
Sharan, Shyam K.
Nussenzweig, André
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/nature18325Metadata
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Chaudhuri, A. R., E. Callen, X. Ding, E. Gogola, A. A. Duarte, J. Lee, N. Wong, et al. 2016. “Replication Fork Stability Confers Chemoresistance in BRCA-deficient Cells.” Nature 535 (7612): 382-387. doi:10.1038/nature18325. http://dx.doi.org/10.1038/nature18325.Abstract
Brca1- and Brca2-deficient cells have reduced capacity to repair DNA double-strand breaks (DSBs) by homologous recombination (HR) 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 HR activity at DSBs. 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 PARPi and cisplatin resistance is associated with replication fork (RF) protection in Brca2-deficient tumor cells that do not develop Brca2 reversion mutations. Disruption of multiple proteins, including PARP1 and CHD4, leads to the same end point of RF protection, highlighting the complexities by which tumor cells evade chemotherapeutic interventions and acquire drug resistance.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4959813/pdf/Terms of Use
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