Replication fork stability confers chemoresistance in BRCA-deficient cells
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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Replication fork stability confers chemoresistance in BRCA-deficient cells. / 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; Konstantinopoulos, Panagiotis A; Cortez, David; Cantor, Sharon B; Fernandez-Capetillo, Oscar; Ge, Kai; Jonkers, Jos; Rottenberg, Sven; Sharan, Shyam K; Nussenzweig, André.
I: Nature, Bind 535, Nr. 7612, 2016, s. 382-7.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Replication fork stability confers chemoresistance in BRCA-deficient cells
AU - Chaudhuri, Arnab Ray
AU - Callen, Elsa
AU - Ding, Xia
AU - Gogola, Ewa
AU - Duarte, Alexandra A
AU - Lee, Ji-Eun
AU - Wong, Nancy
AU - Lafarga, Vanessa
AU - Calvo, Jennifer A
AU - Panzarino, Nicholas J
AU - John, Sam
AU - Day, Amanda
AU - Crespo, Anna Vidal
AU - Shen, Binghui
AU - Starnes, Linda M
AU - de Ruiter, Julian R
AU - Daniel, Jeremy A
AU - Konstantinopoulos, Panagiotis A
AU - Cortez, David
AU - Cantor, Sharon B
AU - Fernandez-Capetillo, Oscar
AU - Ge, Kai
AU - Jonkers, Jos
AU - Rottenberg, Sven
AU - Sharan, Shyam K
AU - Nussenzweig, André
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Journal Article
KW - Research Support, N.I.H., Intramural
KW - Research Support, Non-U.S. Gov't
KW - Research Support, U.S. Gov't, Non-P.H.S.
U2 - 10.1038/nature18325
DO - 10.1038/nature18325
M3 - Journal article
C2 - 27443740
VL - 535
SP - 382
EP - 387
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7612
ER -
ID: 164136217