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MCB Accepts, published online ahead of print on 30 July 2007
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Mol. Cell. Biol. doi:10.1128/MCB.00961-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Activation of BRCA1/BRCA2-associated helicase BACH1 is required for timely progression through S Phase

Easwari Kumaraswamy and Ramin Shiekhattar*

The Wistar Institute, 3601 Spruce Street Philadelphia, PA 19104

* To whom correspondence should be addressed. Email: ramin.shiekhattar{at}crg.es.


   Abstract

BACH1 (also known as FANCJ and BRIP1) is a DNA helicase that directly interacts with the C-terminal BRCT repeat of the breast cancer susceptibility protein, BRCA1. Previous biochemical and functional analysis has suggested a role for BACH1 homolog in C.elegans during DNA replication. Here, we report the association of BACH1 with a distinct BRCA1/BRCA2 containing complex during the S phase of the cell cycle. Depletion of BACH1 or BRCA1 using small interfering RNAs results in delayed entry into the S phase of the cell cycle. Such timely progression through S phase requires the helicase activity of BACH1. Importantly, cells expressing a dominant negative mutation in BACH1 resulting in defective helicase displayed increased activation of DNA-damage checkpoints and genomic instability. BACH1 helicase is silenced during the G1 phase of the cell cycle and is activated through a dephosphorylation event as cells enter S phase. These results point to a critical role for BACH1 helicase activity not only in the timely progression through the S phase but also in maintaining genomic stability.




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