Brca1 is required for maintenance of phospho-chk1 and g2/m arrest during dna cross-link repair in dt40 cells
Madgett, Elizabeth B.
Vandenberg, Cassandra J.
du Plessis, David
Lowndes, Noel F.
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Draga, Margarethe; Madgett, Elizabeth B. Vandenberg, Cassandra J.; du Plessis, David; Kaufmann, Aisling; Werler, Petra; Chakraborty, Prasun; Lowndes, Noel F.; Hiom, Kevin (2015). Brca1 is required for maintenance of phospho-chk1 and g2/m arrest during dna cross-link repair in dt40 cells. Molecular and Cellular Biology 35 (22), 3829-3840
The Fanconi anemia DNA repair pathway is pivotal for the efficient repair of DNA interstrand cross-links. Here, we show that FA-defective (Fancc(-)) DT40 cells arrest in G(2) phase following cross-link damage and trigger apoptosis. Strikingly, cell death was reduced in Fancc(-) cells by additional deletion of the BRCA1 tumor suppressor, resulting in elevated clonogenic survival. Increased resistance to cross-link damage was not due to loss of toxic BRCA1-mediated homologous recombination but rather through the loss of a G(2) checkpoint. This proapoptotic role also required the BRCA1-A complex member ABRAXAS (FAM175A). Finally, we show that BRCA1 promotes G(2) arrest and cell death by prolonging phosphorylation of Chk1 on serine 345 after DNA damage to sustain arrest. Our data imply that DNA-induced cross-link death in cells defective in the FA pathway is dependent on the ability of BRCA1 to prolong cell cycle arrest in G(2) phase.