Carcinogenesis Advance Access published online on November 4, 2007
Carcinogenesis, doi:10.1093/carcin/bgm238
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Phosphorylation-dependent interactions of BLM and 53BP1 are required for their anti-recombinogenic roles during homologous recombination
1 National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India
2 Corresponding author: Sagar Sengupta, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India, Phone: 91-11-26703786, Fax: 91-11-2616 2125, Email: sagar{at}nii.res.in
Mutations in BLM helicase causes Bloom Syndrome, characterized by predisposition to almost all forms of cancer. We have previously demonstrated 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 Chk1 via the Kinetochore Binding Domain (KBD). Wild-type 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. ATR-mediated phosphorylation of BLM at Thr99 is critical for its interaction and subsequent colocalization with 53BP1. Wild-type BLM enhances the interaction and colocalization 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 wild-type 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 (HR).
Key Words: RecQ helicase • ATM • ATR • Kinetochore binding domain • Chk1
Received September 13, 2007; revised October 15, 2007; accepted October 19, 2007.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. B.C. Buonomo, Y. Wu, D. Ferguson, and T. de Lange Mammalian Rif1 contributes to replication stress survival and homology-directed repair J. Cell Biol., November 2, 2009; 187(3): 385 - 398. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Srivastava, P. Modi, V. Tripathi, R. Mudgal, S. De, and S. Sengupta BLM helicase stimulates the ATPase and chromatin-remodeling activities of RAD54 J. Cell Sci., September 1, 2009; 122(17): 3093 - 3103. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-l. Ding, J.-C. Yu, S.-T. Chen, G.-C. Hsu, S.-J. Kuo, Y. H. Lin, P.-E. Wu, and C.-Y. Shen Genetic variants of BLM interact with RAD51 to increase breast cancer susceptibility Carcinogenesis, January 1, 2009; 30(1): 43 - 49. [Abstract] [Full Text] [PDF]
|
|