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BRCA1 function mediates a TRAP/DRIP complex through direct interaction with TRAP220
- Source :
- Oncogene. 23:6000-6005
- Publication Year :
- 2004
- Publisher :
- Springer Science and Business Media LLC, 2004.
-
Abstract
- Breast cancer susceptibility gene 1 (BRCA1) is a tumor suppressor gene mutated in a high percentage of hereditary breast and ovarian cancers. The multifunctional BRCA1 protein acts on cell cycle control, exerting several highly specialized DNA repair processes through diverse domains. Gene regulation through its C-terminal domain (BRCT) is indispensable for BRCA1-mediated tumor suppression, suggesting the possibility that the BRCT domain interacts with co-regulator complexes. Using a biochemical approach with HeLa S3 nuclear extracts, we isolated BRCT-associated complexes and identified one of the purified components as TRAP220. We then performed interaction studies in vivo (co-immunoprecipitation) and in vitro (glutathione S-transferase pull-down assays) and showed that BRCT directly interacted with TRAP220. This in vitro interaction was completely abolished by BRCT point mutations typical of those found in patients with BRCA1 that lack transactivation function. BRCA1 transactivation function was dependent on TRAP220 expression level in a transient expression assay. Moreover, a cell survival assay showed that antisense TRAP220 expression to disrupt endogenous TRAP220 expression significantly reduced the survival rate potentiated by BRCA1 after DNA damage. These results suggested that a TRAP220 complex play an important role as putative co-activator complexes in BRCA1-mediated tumor suppression.
- Subjects :
- Transcriptional Activation
Cancer Research
Tumor suppressor gene
DNA damage
DNA repair
Breast Neoplasms
Biology
medicine.disease_cause
Mediator Complex Subunit 1
Transactivation
Genetics
medicine
Humans
skin and connective tissue diseases
Molecular Biology
Regulation of gene expression
Mediator Complex
BRCA1 Protein
Nuclear Proteins
Cell cycle
Cell biology
BRCT domain
Trans-Activators
Female
Carcinogenesis
DNA Damage
HeLa Cells
Transcription Factors
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 23
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....1cc679a476f5f6fad9588fb8f88b8482