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A naturally occurring allele of BRCA1 coding for a temperature-sensitive mutant protein

Author:
  • T Worley
  • Johan Vallon-Christersson
  • B Billack
  • Åke Borg
  • ANA Monteiro
Publishing year: 2002
Language: English
Pages: 497-501
Publication/Series: Cancer Biology & Therapy
Volume: 1
Issue: 5
Document type: Journal article
Publisher: Landes Bioscience

Abstract english

Recent evidence suggests that the breast and ovarian cancer susceptibility gene product BRCA1 is involved in at least two fundamental cellular processes: transcriptional regulation and DNA repair. However, the mechanism of action of BRCA1 in either of these processes is still unknown. Here, we report the characterization of a disease-predisposing allele of BRCA1, identified in a family with several cases of ovarian cancer, coding for a protein that displays temperature-sensitive activity in transcriptional activation. The mutant protein differs from the wild type protein at a single amino acid, R1 699W that occurs in a region at the N-terminal BRCT domain that is highly conserved among BRCA1 homologs. When the C-terminus of the mutant protein (aa 1560-1863) was fused to a heterologous GAL4 DNA-binding domain and expressed in yeast or mammalian cells, it was able to activate transcription of a reporter gene to levels observed for wild type BRCA1 at the permissive temperature (30degreesC) but exhibited significantly less transcription activity at the restrictive temperature (37degreesC or 39degreesC). Our results indicate that the transcriptional activity of the R1699W mutant can be modulated as a function of temperature and provide a novel experimental approach which can be utilized to dissect the molecular mechanism(s) of BRCA1 in processes related to transcription.

Keywords

  • Cancer and Oncology
  • temperature-sensitive mutants
  • transcription
  • BRCA1
  • yeast
  • BRCT
  • domain
  • ovarian cancer

Other

Published
  • ISSN: 1538-4047
Åke Borg
Åke Borg
E-mail: ake [dot] borg [at] med [dot] lu [dot] se

Principal investigator

Oncology and Pathology, MV

+46 46 275 25 52

MV 404 C21B2

90

Project manager

Familial Breast Cancer

90

Professor

Oncology and Pathology, MV

MV 404 C21C2

90