Regulation of BRCA1 phosphorylation by interaction with protein phosphatase 1alpha.

Published

Journal Article

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 alpha (PP1alpha) catalytic subunit and endogenous PP1alpha dephosphorylate GST-BF4-P. Inhibitor 2 abolishes this activity. Overexpression of PP1alpha partially inhibits hyperphosphorylation of BRCA1 after ionizing radiation, indicating that PP1alpha dephosphorylates BRCA1 in vivo. BRCA1 and PP1alpha reciprocally coimmunoprecipitate, and a glutathione S-transferase pull-down assay shows that PP1alpha catalytic subunit associates directly with the BF4 region of BRCA1. In addition, BRCA1 inhibits PP1alpha activity. Therefore, BRCA1 is both a substrate and a regulator of PP1alpha. The interaction between BRCA1 and PP1alpha thus may play a role in DNA damage repair and cell cycle progression.

Full Text

Duke Authors

Cited Authors

  • Liu, Y; Virshup, DM; White, RL; Hsu, L-C

Published Date

  • November 15, 2002

Published In

Volume / Issue

  • 62 / 22

Start / End Page

  • 6357 - 6361

PubMed ID

  • 12438214

Pubmed Central ID

  • 12438214

International Standard Serial Number (ISSN)

  • 0008-5472

Language

  • eng

Conference Location

  • United States