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Carcinogenesis Advance Access originally published online on November 4, 2007
Carcinogenesis 2008 29(1):52-61; doi:10.1093/carcin/bgm238
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Phosphorylation-dependent interactions of BLM and 53BP1 are required for their anti-recombinogenic roles during homologous recombination

Vivek Tripathi, Sarabpreet Kaur and Sagar Sengupta*

National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India

* To whom correspondence should be addressed. Tel: +91 11 2670 3786; Fax: +91 11 2674 2125; Email: sagar{at}nii.res.in

Mutations in bloom helicase protein (BLM) helicase cause Bloom syndrome, characterized by predisposition to almost all forms of cancer. We have demonstrated previously that endogenous BLM, signal transducer 53BP1 and RAD51 are present in a complex during replication stress. Using full-length recombinant proteins, we now provide evidence that these proteins physically interact. BLM interacts with checkpoint kinase (Chk) 1 via the kinetochore-binding domain (KBD). Wild-type (WT) Chk1 phosphorylates 53BP1 in the KBD, both in vitro and in vivo during replication stress. Chk1-mediated phosphorylation of 53BP1 enhances its binding to BLM and is required for the accumulation of 53BP1 at the site of stalled replication. 53BP1, in turn, binds to the N-terminal domain of BLM. Ataxia telangiectasia and Rad3 related (ATR)-mediated phosphorylation of BLM at Thr99 is critical for its interaction and subsequent co-localization with 53BP1. WT BLM enhances the interaction and co-localization between 53BP1 and RAD51 during replication arrest. Interactions between the three proteins have functional consequences. Non-binding or phosphorylation-deficient mutants of BLM and 53BP1 fail to demonstrate the anti-recombinogenic property of the WT counterparts. Consequently, these mutants cause elevation of endogenous RAD51 foci formation. These results provide evidence that the phosphorylation-mediated interactions between BLM, 53BP1 and RAD51 are required for their regulatory roles during homologous recombination.

Abbreviations: ATP, adenosine triphosphate; ATR, ataxia telangiectasia and Rad3 related; ATM, ataxia telangiectasia mutated; BFP, blue fluorescent protein; BLM, bloom helicase protein; BS, Bloom syndrome; cDNA, complementary DNA; Chk, checkpoint kinase; GAR, glycine–arginine rich; GFP, green fluorescent protein; GST, glutathione S-transferase; HR, homologous recombination; HU, hydroxyurea; IF, immunofluorescence; IP, immunoprecipitation; IR, ionizing radiation; KBD, kinetochore-binding domain; NB, nuclear body; NHF, normal human fibroblast; PML, promyelocytic leukemia; PW, post-wash; WT, wild-type

Received September 13, 2007; revised October 15, 2007; accepted October 19, 2007.


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