An Emerging Model for BAP1’s Role in Regulating Cell Cycle Progression

• Authors: Ziad M. Eletr, Emory University; Keith D Wilkinson, Emory University
• Journal Title: Cell Biochemistry and Biophysics
• Volume: Volume 60, Number 1-2
• Publisher: Springer (part of Springer Nature): Springer Open Choice Hybrid Journals | 2011-06, Pages 3-11
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1007/s12013-011-9184-6
• Subjects: Biology, Cell
• Keywords: BAP1; Ubiquitin C-terminal hydrolase; Protease; Deubiquitylase

Abstract

BRCA1-associated protein-1 (BAP1) is a 729 residue, nuclear-localized deubiquitinating enzyme (DUB) that displays tumor suppressor properties in the BAP1-null NCI-H226 lung carcinoma cell line. Studies that have altered BAP1 cellular levels or enzymatic activity have reported defects in cell cycle progression, notably at the G1/S transition. Recently BAP1 was shown to associate with the transcriptional regulator host cell factor 1 (HCF-1). The BAP1/HCF-1 interaction is mediated by the HCF-1 Kelch domain and an HCF-1 binding motif (HBM) within BAP1. HCF-1 is modified with ubiquitin in vivo, and ectopic studies suggest BAP1 deubiquitinates HCF-1. HCF-1 is a chromatin-associated protein thought to both activate and repress transcription by linking appropriate histone-modifying enzymes to a subset of transcription factors. One known role of HCF-1 is to promote cell cycle progression at the G1/S boundary by recruiting H3K4 histone methyltransferases to the E2F1 transcription factor so that genes required for S-phase can be transcribed. Given the robust associations between BAP1/HCF-1 and HCF-1/E2Fs, it is reasonable to speculate that BAP1 influences cell proliferation at G1/S by co-regulating transcription from HCF-1/E2F-governed promoters