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Published on: August 12, 2015
BRD7 is a candidate tumour suppressor gene required for p53 function
Jarno Drost1, Fiamma Mantovani, Francesca Tocco
1The Netherlands Cancer Institute, Division of Gene Regulation, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands.
Abstract:
Oncogene-induced senescence is a p53-dependent defence mechanism against uncontrolled proliferation. Consequently, many human tumours harbour p53 mutations and others show a dysfunctional p53 pathway, frequently by unknown mechanisms. Here we identify BRD7 (bromodomain-containing 7) as a protein whose inhibition allows full neoplastic transformation in the presence of wild-type p53. In human breast tumours harbouring wild-type, but not mutant, p53 the BRD7 gene locus was frequently deleted and low BRD7 expression was found in a subgroup of tumours. Functionally, BRD7 is required for efficient p53-mediated transcription of a subset of target genes. BRD7 interacts with p53 and p300 and is recruited to target gene promoters, affecting histone acetylation, p53 acetylation and promoter activity. Thus, BRD7 suppresses tumorigenicity by serving as a p53 cofactor required for the efficient induction of p53-dependent oncogene-induced senescence.
Insights
Bromodomain-containing 7 (BRD7) acts as a tumor suppressor by enabling p53-dependent cellular senescence. Loss of BRD7 facilitates cancer development even with functional p53, highlighting its critical role in preventing uncontrolled cell growth.
Area of Science:
- Molecular Biology
- Cancer Research
- Cellular Biology
Background:
- Oncogene-induced senescence is a crucial p53-dependent tumor suppression mechanism.
- Many human tumors exhibit p53 mutations or pathway dysfunction, often through unknown mechanisms.
- Understanding factors that bypass p53-mediated tumor suppression is vital for cancer therapy.
Purpose of the Study:
- To identify novel proteins involved in p53-dependent oncogene-induced senescence.
- To elucidate the role of BRD7 (bromodomain-containing 7) in preventing neoplastic transformation.
- To investigate the mechanism by which BRD7 interacts with the p53 pathway.
Main Methods:
- Analysis of BRD7 gene deletions and expression in human breast tumors.
- Investigating the functional requirement of BRD7 in p53-mediated transcription.
- Biochemical assays to study BRD7 interaction with p53 and p300.
- Chromatin immunoprecipitation to assess BRD7 recruitment to target gene promoters.
Main Results:
- BRD7 inhibition promotes neoplastic transformation in wild-type p53 cells.
- BRD7 gene deletions and low expression correlate with wild-type p53 status in breast tumors.
- BRD7 acts as a cofactor for p53, enhancing transcription of specific target genes.
- BRD7 influences histone and p53 acetylation at target gene promoters.
Conclusions:
- BRD7 is a critical tumor suppressor that functions as a p53 cofactor.
- BRD7 is essential for the induction of p53-dependent oncogene-induced senescence.
- BRD7 deficiency contributes to tumorigenesis by impairing p53-mediated cell cycle arrest.
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