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Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1.

Protein ubiquitination provides an efficient and reversible mechanism to regulate cell cycle progression and checkpoint control. Numerous regulatory proteins direct the addition of ubiquitin to lysine residues on target proteins, and these are countered by an army of deubiquitinating enzymes (DUBs). BRCA1-associated protein-1 (Bap1) is a ubiquitin carboxy-terminal hydrolase and is frequently mutated in lung and sporadic breast tumors. Bap1 can suppress growth of lung cancer cells in athymic nude mice and this requires its DUB activity. We show here that Bap1 interacts with host cell factor 1 (HCF-1), a transcriptional cofactor found in a number of important regulatory complexes. Bap1 binds to the HCF-1 beta-propeller using a variant of the HCF-binding motif found in herpes simplex virus VP16 and other HCF-interacting proteins. HCF-1 is K48 and K63 ubiquitinated, with a major site of linkage at lysines 1807 and 1808 in the HCF-1(C) subunit. Expression of a catalytically inactive version of Bap1 results in the selective accumulation of K48 ubiquitinated polypeptides. Depletion of Bap1 using small interfering RNA results in a modest accumulation of HCF-1(C), suggesting that Bap1 helps to control cell proliferation by regulating HCF-1 protein levels and by associating with genes involved in the G(1)-S transition.

Pubmed ID: 19188440


  • Misaghi S
  • Ottosen S
  • Izrael-Tomasevic A
  • Arnott D
  • Lamkanfi M
  • Lee J
  • Liu J
  • O'Rourke K
  • Dixit VM
  • Wilson AC


Molecular and cellular biology

Publication Data

April 27, 2009

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM61139
  • Agency: NIGMS NIH HHS, Id: R01 GM061139
  • Agency: NCRR NIH HHS, Id: S10 RR017970

Mesh Terms

  • Animals
  • Binding Sites
  • Cell Cycle Proteins
  • Cell Proliferation
  • Host Cell Factor C1
  • Interphase
  • Mice
  • Protein Binding
  • Ubiquitin Thiolesterase
  • Ubiquitin-Protein Ligases