Gadd45 Mediates the BRCA1-Induced Cell Cycle Arrest
Abstract
Breast cancer susceptibility gene; BRCA1 has been implicated in maintenance of genomic integrity. Deregulation of genomic stability is closely associated with tumorigenesis. However, the molecular mechanism by which BRCA1 participates in maintaining genomic fidelity remains unclear. Our current study has demonstrated that BRCA1 transcriptionally activates GADD45, a p53-regulated and DNA damage-inducible gene that may play an important role in cell cycle checkpoints, apoptosis and DNA repair. Activation of the GADD45 gene by BRCA1 is independent of tumor suppressor p53. Most recent findings demonstrate that upregulation of GADD45 mRNA by BRCA1 is mediated through activation of the GADD45 promoter. Using 5'-deletion analysis, the BRCA1-regulatory elements are mapped at the region of the GADD45 promoter from -107 to -57. Deletion of this region abrogates the BRCA1 activation of the GADD45 promoter. Inspection of DNA sequence shows that there are two OCT-I and CAAT motifs located at this region. Mutations of OCT-1 and CAAT motifs also disrupt BRCA1 activation of the GADD45 promoter, indicating these two motifs are involved in the BRCA1 activation of the GADD45 promoter. The current study demonstrates a novel pathway (BRCA1-GADD45) involved in cellular response to DNA damage.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2001
- Accession Number
- ADA396673
Entities
People
- Qimin Zhan
Organizations
- University of Pittsburgh