This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liu, Y. Articles by Hsu, L.-C. Search for Related Content PubMed PubMed Citation Articles by Liu, Y. Articles by Hsu, L.-C.

Regulation of BRCA1 Phosphorylation by Interaction with Protein Phosphatase 1¹

Department of Oncological Sciences, University of Utah, Salt Lake City, Utah 84112

Numerous reports have revealed that the tumor suppressor BRCA1 may play an important role in DNA damage repair. BRCA1 is expressed and phosphorylated during cell cycle progression and after DNA damage. BRCA1 is hypophosphorylated in G₀-G₁ and probably during mitosis as well. Kinases known to phosphorylate BRCA1 include cyclin-dependent kinase 2, as well as ataxia telangiectasia-mutated (ATM) and ATM and Rad3-related kinase (ATR), which function in G₂ checkpoint control. However, protein phosphatases responsible for dephosphorylation of BRCA1 had yet to be identified. hCds1, which acts downstream of ATM, also phosphorylates a BRCA1 fragment containing amino acids 759-1064 [BRCA1 fragment 4 (BF4)]. We have used a GST-BF4 protein phosphorylated by hCds1 [glutathione S-transferase (GST)-BF4-P] as a substrate to identify potential phosphatases responsible for BRCA1 dephosphorylation. Data presented here show that both recombinant protein phosphatase 1 (PP1) catalytic subunit and endogenous PP1 dephosphorylate GST-BF4-P. Inhibitor 2 abolishes this activity. Overexpression of PP1 partially inhibits hyperphosphorylation of BRCA1 after ionizing radiation, indicating that PP1 dephosphorylates BRCA1 in vivo. BRCA1 and PP1 reciprocally coimmunoprecipitate, and a glutathione S-transferase pull-down assay shows that PP1 catalytic subunit associates directly with the BF4 region of BRCA1. In addition, BRCA1 inhibits PP1 activity. Therefore, BRCA1 is both a substrate and a regulator of PP1. The interaction between BRCA1 and PP1 thus may play a role in DNA damage repair and cell cycle progression.

This article has been cited by other articles:

				S. Sankaran, D. E. Crone, R. E. Palazzo, and J. D. Parvin Aurora-A Kinase Regulates Breast Cancer Associated Gene 1 Inhibition of Centrosome-Dependent Microtubule Nucleation Cancer Res., December 1, 2007; 67(23): 11186 - 11194. [Abstract] [Full Text] [PDF]

				M. C. Korrapati, J. Chilakapati, E. A. Lock, J. R. Latendresse, A. Warbritton, and H. M. Mehendale Preplaced cell division: a critical mechanism of autoprotection against S-1,2-dichlorovinyl-L-cysteine-induced acute renal failure and death in mice Am J Physiol Renal Physiol, August 1, 2006; 291(2): F439 - F455. [Abstract] [Full Text] [PDF]

				J. Yang, Y. Yu, H. E. Hamrick, and P. J. Duerksen-Hughes ATM, ATR and DNA-PK: initiators of the cellular genotoxic stress responses Carcinogenesis, October 1, 2003; 24(10): 1571 - 1580. [Abstract] [Full Text] [PDF]