BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage

Ronit I. Yarden, Sherly Pardo-Reoyo, Magda Sgagias, Kenneth H Cowan, Lawrence C. Brody

Research output: Contribution to journalArticle

359 Citations (Scopus)

Abstract

The breast cancer tumor-suppressor gene, BRCA1, encodes a protein with a BRCT domain-a motif that is found in many proteins that are implicated in DNA damage response and in genome stability. Phosphorylation of BRCA1 by the DNA damage-response proteins ATM, ATR and hCds1/Chk2 changes in response to DNA damage and at replication-block checkpoints. Although cells that lack BRCA1 have an abnormal response to DNA damage, the exact role of BRCA1 in this process has remained unclear. Here we show that BRCA1 is essential for activating the Chk1 kinase that regulates DNA damage-induced G2/M arrest. Thus, BRCA1 controls the expression, phosphorylation and cellular localization of Cdc25C and Cdc2/cyclin B kinase-proteins that are crucial for the G2/M transition. We show that BRCA1 regulates the expression of both Wee 1 kinase, an inhibitor of Cdc2/cyclin B kinase, and the 14-3-3 family of proteins that sequesters phosphorylated Cdc25C and Cdc2/cyclin B kinase in the cytoplasm. We conclude that BRCA1 regulates key effectors that control the G2/M checkpoint and is therefore involved in regulating the onset of mitosis.

Original languageEnglish (US)
Pages (from-to)285-289
Number of pages5
JournalNature Genetics
Volume30
Issue number3
DOIs
StatePublished - Jan 1 2002

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DNA Damage
Cyclin B
Phosphotransferases
Tumor Suppressor Genes
Ataxia Telangiectasia Mutated Proteins
Phosphorylation
Breast Neoplasms
14-3-3 Proteins
Genomic Instability
Mitosis
Protein Kinases
Cytoplasm
Proteins
Checkpoint Kinase 1

ASJC Scopus subject areas

  • Genetics

Cite this

BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage. / Yarden, Ronit I.; Pardo-Reoyo, Sherly; Sgagias, Magda; Cowan, Kenneth H; Brody, Lawrence C.

In: Nature Genetics, Vol. 30, No. 3, 01.01.2002, p. 285-289.

Research output: Contribution to journalArticle

Yarden, RI, Pardo-Reoyo, S, Sgagias, M, Cowan, KH & Brody, LC 2002, 'BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage', Nature Genetics, vol. 30, no. 3, pp. 285-289. https://doi.org/10.1038/ng837
Yarden, Ronit I. ; Pardo-Reoyo, Sherly ; Sgagias, Magda ; Cowan, Kenneth H ; Brody, Lawrence C. / BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage. In: Nature Genetics. 2002 ; Vol. 30, No. 3. pp. 285-289.
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