A requirement for breast-cancer-associated gene 1 (BRCA1) in the spindle checkpoint

Rui Hong Wang, Hongtao Yu, Chu Xia Deng

Research output: Contribution to journalArticle

115 Scopus citations

Abstract

BRCA1-associated breast cancer exhibits significantly higher levels of chromosomal abnormalities than sporadic breast cancers. However, the molecular mechanisms regarding the roles of BRCA1 in maintaining genome integrity remain elusive. By using a mouse model deficient for Brca1 full-length isoform (Brca1Δ11/Δ11), we found that Brca1 Δ11/Δ11 cells displayed decreased expression of a number of genes that are involved in the spindle checkpoint, including Mad2, which is a key component of spindle checkpoint that inhibits anaphase-promoting complex. We showed that Brca1Δ11/Δ11 cells failed to arrest at metaphase in the presence of nocodazole and underwent apoptosis because of activation of p53. Consistently, reconstitution of Mad2 in Brca1 Δ11/Δ11 cells partially restored the spindle checkpoint and attenuated apoptosis. By using UBR60 cells, which carry tetracycline- regulated expression of BRCA1, we demonstrated that BRCA1 binds to transcription factor OCT-1 and up-regulates the transcription of MAD2. Furthermore, we showed that the induction of BRCA1 to endogenous MAD2 or transfected MAD2 luciferase reporter in UBR60 cells was completely inhibited by acute suppression of BRCA1 by RNA interference. These data reveal a role of BRCA1 in maintaining genome integrity by interplaying with p53 and genes that are involved in the spindle checkpoint and apoptosis.

Original languageEnglish (US)
Pages (from-to)17108-17113
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number49
DOIs
StatePublished - Dec 7 2004

Keywords

  • Cell cycle
  • Genetic instability
  • Mad2
  • OCT-1
  • p53

ASJC Scopus subject areas

  • General

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