BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage.
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 Wee1 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.
Yarden
Ronit I
RI
Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Pardo-Reoyo
Sherly
S
Sgagias
Magda
M
Cowan
Kenneth H
KH
Brody
Lawrence C
LC
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004789:Enzyme Activation; D005455:Fluorescent Antibody Technique; D016195:G2 Phase / Q000502:physiology*; D019398:Genes, BRCA1 / Q000502:physiology*; D006801:Humans; D008938:Mitosis / Q000502:physiology*; D011233:Precipitin Tests; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1