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

Worley, T; Vallon-Christersson, Johan LU ; Billack, B; Borg, Åke LU and Monteiro, ANA (2002) In Cancer Biology & Therapy 1(5). p.497-501
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
temperature-sensitive mutants, transcription, BRCA1, yeast, BRCT, domain, ovarian cancer
in
Cancer Biology & Therapy
volume
1
issue
5
pages
497 - 501
publisher
Landes Bioscience
external identifiers
  • wos:000180996500009
  • scopus:0346554742
ISSN
1538-4047
language
English
LU publication?
yes
id
4846c498-1964-4816-9ba2-fe1889516159 (old id 318314)
alternative location
http://www.landesbioscience.com/journals/cbt/article/worley1-5.pdf
date added to LUP
2007-11-09 16:04:23
date last changed
2017-08-20 03:31:06
@article{4846c498-1964-4816-9ba2-fe1889516159,
  abstract     = {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.},
  author       = {Worley, T and Vallon-Christersson, Johan and Billack, B and Borg, Åke and Monteiro, ANA},
  issn         = {1538-4047},
  keyword      = {temperature-sensitive mutants,transcription,BRCA1,yeast,BRCT,domain,ovarian cancer},
  language     = {eng},
  number       = {5},
  pages        = {497--501},
  publisher    = {Landes Bioscience},
  series       = {Cancer Biology & Therapy},
  title        = {A naturally occurring allele of BRCA1 coding for a temperature-sensitive mutant protein},
  volume       = {1},
  year         = {2002},
}