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Phosphorylation of human Fen1 by cyclin-dependent kinase modulates its role in replication fork regulation.

Cyclin-dependent kinase (Cdk) Cdk1-Cyclin A can phosphorylate Flap endonuclease 1 (Fen1), a key-enzyme of the DNA replication machinery, in late S phase. Cdk1-cyclin A forms a complex in vitro and in vivo with Fen1. Furthermore, Fen1 phosphorylation is detected in vivo and depends upon Cdks activity. As a functional consequence of phosphorylation by Cdk1-Cyclin A in vitro, endo- and exonuclease activities of Fen1 are reduced whereas its DNA binding is not affected. Moreover, phosphorylation of Fen1 by Cdk1-Cyclin A abrogates its proliferating cell nuclear antigen (PCNA) binding thus preventing stimulation of Fen1 by PCNA. Concomitantly, human cells expressing the S187A mutant defective for Cdk1-Cyclin A phosphorylation accumulate in S phase consistent with a failure in cell cycle regulation through DNA replication. Our results suggest a novel regulatory role of Cdks onto the end of S phase by targeting directly a key enzyme involved in DNA replication.

Pubmed ID: 12853968

Authors

  • Henneke G
  • Koundrioukoff S
  • Hübscher U

Journal

Oncogene

Publication Data

July 10, 2003

Associated Grants

None

Mesh Terms

  • Adenosine Triphosphate
  • CDC2 Protein Kinase
  • CDC2-CDC28 Kinases
  • Cyclin A
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases
  • DNA
  • DNA Replication
  • Endodeoxyribonucleases
  • Flap Endonucleases
  • HeLa Cells
  • Humans
  • Phosphorylation
  • Proliferating Cell Nuclear Antigen
  • Protein-Serine-Threonine Kinases
  • S Phase