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PMID:11953320

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Citation

Sarcevic, B, Mawson, A, Baker, RT and Sutherland, RL (2002) Regulation of the ubiquitin-conjugating enzyme hHR6A by CDK-mediated phosphorylation. EMBO J. 21:2009-18

Abstract

Cell cycle progression in eukaryotes is mediated by phosphorylation of protein substrates by the cyclin-dependent kinases (CDKs). We screened a cDNA library by solid-phase phosphorylation and isolated hHR6A as a CDK2 substrate. hHR6A is the human homologue of the product of the Saccharomyces cerevisiae RAD6/UBC2 gene, a member of the family of ubiquitin-conjugating enzymes. hHR6A is phosphorylated in vitro by CDK-1 and -2 on Ser120, a residue conserved in all hHR6A homologues, resulting in a 4-fold increase in its ubiquitin-conjugating activity. In vivo, hHR6A phosphorylation peaks during the G2/M phase of cell cycle transition, with a concomitant increase in histone H2B ubiquitylation. Mutation of Ser120 to threonine or alanine abolished hHR6A activity, while mutation to aspartate to mimic phosphorylated serine increased hHR6A activity 3-fold. Genetic complementation studies in S.cerevisiae demonstrated that hHR6A Ser120 is critical for cellular proliferation. This is the first study to demonstrate regulation of UBC function by phosphorylation on a conserved residue and suggests that CDK-mediated phosphorylation of hHR6A is an important regulatory event in the control of cell cycle progression.

Links

PubMed PMC125963 Online version:10.1093/emboj/21.8.2009

Keywords

Amino Acid Sequence; Animals; Binding Sites; CDC2-CDC28 Kinases; CHO Cells; Cell Cycle; Cell Division; Cricetinae; Cyclin A/genetics; Cyclin A/metabolism; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinases/genetics; Cyclin-Dependent Kinases/metabolism; G2 Phase; Histones/metabolism; Humans; Ligases/genetics; Ligases/metabolism; Mitosis; Molecular Sequence Data; Phosphorylation; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; Saccharomyces cerevisiae Proteins; Sequence Homology, Amino Acid; Serine/metabolism; Ubiquitin/metabolism; Ubiquitin-Conjugating Enzymes

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:UBE2A

enables

GO:0004842: ubiquitin-protein transferase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:UBE2A

involved_in

GO:0008284: positive regulation of cell population proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:UBE2A

involved_in

GO:0051865: protein autoubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:UBE2A

involved_in

GO:0033522: histone H2A ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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