Gadd45¦Á In Genome Stability And Gene Expression Regulation

The common character of human tumor is genomic instability. One of the major types for genomic instability is chromosomal instability(CIN), which is mainly caused by mutations of genes that maintain cell genomic stability. Of the many intrinsic and extrinsic types of DNA damage that can be created inside mammalian cells, such as exogenous physic and chemical agents (irradiation, UV and certain carcinogens), or cellular sources such as oxidative damage or replication blocks in the DNA. DNA damage is a relatively common event in the life of a cell, and may lead to mutation, carcinogenesis, or cell death. In response to DNA damage, cell will undergo growth arrest, presumably to allow time for DNA repair. There are at least two mechanisms for the repair of DSB, homologous recombination (HR) and non-homologous end-joining (NHEJ). Normally,cells that finish DNA repair return to cell cycle, but other cells without complete DNA repair will be removed by apoptosis before DNA replication or chromosal segregion. However, if apoptosis is inhibited due to inactivation of regulatory machinery. This stuation increases the risk of CIN at several levels, and cells that are sufficiently fit to survive can be at a growth advantage, which lead to cancer. Gadd45a and BRCA1 are two important proteins involved in the control of cell cycle progression and apoptosis, both of them play key roles in homologous recombination.In this paper, we have found that when knockdown Gadd45a, a large deletion is shown on Y chromosome long arm(Yq). The Y chromosome is particularly vulnerable to DNA damage, partly because of its genetic structure and partly because it cannot correct double-stranded DNA deletions by homologous recombination. We then further confirmed that Gadd45a can be involved in the regulation of BRCA1 expression at the transcriptional level, but Gadd45a does not increase its promoter activity, Gadd45a protein also can not binding BRCA1 promoter directly. Cell immunofluorescence experiments show that Gadd45a does not affect BRCA1 subcellular localization.These studies have demostrated that Gadd45a can regulate BRCA1 expression in mRNA and protein expression level, providing a novel find that BRCA1 may be regulated by its previously-defined downstream gene Gadd45α. However the mechanisms regarding Gadd45a regulation of BRCA1 remain to be defined.