Universität zu Köln

Draga, Margarethe, Madgett, Elizabeth B., Vandenberg, Cassandra J., du Plessis, David, Kaufmann, Aisling, Werler, Petra, Chakraborty, Prasun, Lowndes, Noel F. and Hiom, Kevin (2015). BRCA1 Is Required for Maintenance of Phospho-Chk1 and G(2)/M Arrest during DNA Cross-Link Repair in DT40 Cells. Mol. Cell. Biol., 35 (22). S. 3829 - 3841. WASHINGTON: AMER SOC MICROBIOLOGY. ISSN 1098-5549

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Draga, Margarethe UNSPECIFIED UNSPECIFIED UNSPECIFIED Madgett, Elizabeth B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vandenberg, Cassandra J. UNSPECIFIED UNSPECIFIED UNSPECIFIED du Plessis, David UNSPECIFIED UNSPECIFIED UNSPECIFIED Kaufmann, Aisling UNSPECIFIED UNSPECIFIED UNSPECIFIED Werler, Petra UNSPECIFIED UNSPECIFIED UNSPECIFIED Chakraborty, Prasun UNSPECIFIED UNSPECIFIED UNSPECIFIED Lowndes, Noel F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hiom, Kevin UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-388883
DOI:	10.1128/MCB.01497-14
Journal or Publication Title:	Mol. Cell. Biol.
Volume:	35
Number:	22
Page Range:	S. 3829 - 3841
Date:	2015
Publisher:	AMER SOC MICROBIOLOGY
Place of Publication:	WASHINGTON
ISSN:	1098-5549
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language FANCONI-ANEMIA PATHWAY; HOMOLOGOUS RECOMBINATION; BREAST-CANCER; DAMAGE RESPONSE; END RESECTION; PROTEIN; CYCLE; CHECKPOINT; FANCD2; PHASE Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/38888