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

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

doi:10.1038/ng837

Cited by 447 publications

(388 citation statements)

References 23 publications

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“…In contrast, the ATM-dependent IR inducible S-phase checkpoint required S1387 of BRCA1 but not S1423. And, as noted above, BRCA1 regulation of the G2/M DNA damage checkpoint occurred through its ability to activate the Chk1 kinase and, thereby, induce molecular events downstream of Chk1 (Yarden et al, 2002).…”

Section: Functional Activities Of Brca1 Cell Cycle Regulation and Gromentioning

confidence: 83%

“…The ability of BRCA1 to rescue cell survival following IR appears to be dependent, in part, on the S988 phosphorylation. Finally, it was demonstrated that funcional BRCA1 is required for the activation of Chk1 kinase, a major component of the DNA damage-responsive G2/M cell cycle checkpoint (Yarden et al, 2002) (see below). Li et al (2000) have described another potential functional interaction between ATM and BRCA1 in response to IR and other genotoxic stresses.…”

Section: Functional Activities Of Brca1 Cell Cycle Regulation and Gromentioning

confidence: 99%

See 1 more Smart Citation

BRCA1 gene in breast cancer

Rosen

Fan

Pestell

et al. 2003

Journal Cellular Physiology

241

195

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The BRCA1 gene was identified and cloned in 1994 based on its linkage to early onset breast cancer and breast-ovarian cancer syndromes in women. While inherited mutations of BRCA1 are responsible for about 40-45% of hereditary breast cancers, these mutations account for only 2-3% of all breast cancers, since the BRCA1 gene is rarely mutated in sporadic breast cancers. However, BRCA1 expression is frequently reduced or absent in sporadic cancers, suggesting a much wider role in mammary carcinogenesis. Since BRCA1 was cloned in 1994, its molecular function has been the subject of intense investigation. These studies have revealed multiple functions of the BRCA1 that may contribute to its tumor suppressor activity, including roles in: cell cycle progression, several highly specialized DNA repair processes, DNA damage-responsive cell cycle checkpoints, regulation of a set of specific transcriptional pathways, and apoptosis. Many of these functions are linked to protein:protein interactions involving different portions of the 1,863 amino acid (aa) BRCA1 protein. BRCA1 functions in cell cycle progression and the DNA damage response appear to be regulated by distinct and specific phosphorylation events, but the molecular pathways activated by these phosphorylations are only beginning to be unraveled. In addition, the reason that BRCA1 mutation carriers develop specific tumor types (breast and ovarian cancers in women and possibly prostate cancers in men) is not clearly understood. Elucidation of the precise molecular functions of the BRCA1 gene product will greatly enhance our understanding of the pathogenesis of hereditary as well as sporadic mammary carcinogenesis.

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Section: Functional Activities Of Brca1 Cell Cycle Regulation and Gromentioning

confidence: 83%

Section: Functional Activities Of Brca1 Cell Cycle Regulation and Gromentioning

confidence: 99%

BRCA1 gene in breast cancer

Rosen

Fan

Pestell

et al. 2003

Journal Cellular Physiology

241

195

View full text Add to dashboard Cite

show abstract

“…Interestingly, Claspin levels are lower in BRCA1-deficient cells, indicating that the BRCA1-pathway may be involved in regulation of Claspin. As BRCA1-deficient cells have a defect in Chk1 activation (Yarden et al, 2002), the lower Claspin levels are possibly due to a defect in Chk1 activation. This agrees with our observation that blocking Chk1 activity in wild-type BRCA1 reconstituted cells inhibits the BRCA1-dependent increase of Claspin expression in these cells.…”

Section: Discussionmentioning

confidence: 99%

“…HCC1937 cells have a defect in Chk1 activation (Yarden et al, 2002), since BRCA1 is required for efficient Chk1 activation following DNA damage. One possible explanation is that the reduced levels of Claspin in HCC1937 cells are due to the lower levels of activated Chk1 in these cells.…”

Section: Chk1 Regulates Claspin Levelsmentioning

confidence: 99%

Chk1 is required to maintain Claspin stability

2006

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“…P21 can specifically inhibit nuclear activity of Cdc2-Cyclin B, whereas 14-3-3 sequesters Cdc2-Cyclin B preventing it from entering the nucleus. The G2/M checkpoint also upregulates Wee1, which leads to an increase in inhibitory phosphorylation on Cdk1-Cyclin B (Yarden et al, 2002). Furthermore, ATM and ATR dependent Plk1 inactivation has been shown, which most likely prevents activation of Cdc25C by phosphorylation (Smits et al, 2000;van Vugt et al, 2001).…”

Section: G2/m Phase Transition Checkpointmentioning

confidence: 99%

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

Smith¹,

Dejsuphong

Balestrini³

et al. 2009

Nat Cell Biol

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The effects of ATM and ATR signalling induced by chromosomal breakage have been described extensively in modulating cell cycle progression up to the onset of mitosis.However, DNA damage checkpoint responses in mitotic cells are not well understood.This thesis reports on the effects of double strand breaks on the progression of mitosis.We found ATM and ATR activation can occur in mitotic Xenopus laevis egg extract and the induction of ATM and ATR by chromosomal breakages inhibits spindle assembly in both Xenopus egg extract and somatic cells. The delay in mitotic progression induced by ATM and ATR was found not to involve major spindle assembly factors activities such as, Cdk1, Plx1 and RCC1/Ran-GTP. However, normal anastral spindles formation around linear DNA coated beads, which can activate ATM and ATR, linked centrosome-driven spindle assembly to ATM and ATR dependent spindle defects. cDNA expression library screening was undertaken to identify novel ATM and ATR targets in this mitotic checkpoint pathway, through which the novel centrosomal protein XCEP63 was identified as a likely candidate. Data obtained from depletion and reconstitution of XCEP63 in Xenopus egg extract established that normal centrosome-driven spindle assembly requires XCEP63. Moreover, ATM and ATR phosphorylates XCEP63 on serine 560 and promotes delocalisation from the centrosome. ATM and ATR inhibition or addition of non-phosphorylable XCEP63 recombinant protein mutated at serine 560 prevents spindle assembly abnormalities.These findings suggest that ATM and ATR regulate mitotic events by targeting XCEP63 and centrosome-dependent spindle assembly. This pathway may provide support for DNA repair processes or regulate cell survival in the presence of mitotic DNA damage. 3

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

Cited by 447 publications

References 23 publications

BRCA1 gene in breast cancer

BRCA1 gene in breast cancer

Chk1 is required to maintain Claspin stability

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

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