In organs that require continuous cellular proliferation for homeostasis, such as the hematopoietic system, genotoxic or oncogenic stress can lead to cell cycle withdrawal. While several key proteins mediating stress-induced cell cycle withdrawal have been identified, our understanding of the molecular pathways linking exposure to stress and transcriptional repression of cell cycle genes remains incomplete. Here, we utilize deletion of the HDAC associated Sin3B to impair the induction of permanent cell cycle withdrawl in a variety of stress conditions to better under stand these molecular pathways. Through microarray analysis, we found Sin3B is required for the activation of the Senescence Associated Secretory Phenotype (SASP) and regulates a set of nuclear encoded mitochondrial genes. In addition, we identified potential novel markers of senescence to better identify senescent cells both in vivo and in vitro. Furthermore, we demonstrate that Bmi-1 directly represses the expression of the chromatin-associated Sin3B corepressor. Exposure to stress releases Bmi-1 from the Sin3B locus, resulting in Sin3B accumulation and subsequent cell cycle withdrawal. Importantly, Sin3B is required for cell cycle exit triggered by loss of Bmi-1, both in fibroblasts and in hematopoietic stem cells, pointing to a novel mechanism for mediating Bmi-1 biological functions. Finally, in line with our observation that Sin3B mediates stress response in the hematopoietic system, mice genetically inactivated for Sin3B are protected from the deleterious effects of γ-irradiation, thus uncovering a central function of Sin3B in hematopoietic stem cell exhaustion and radio-sensitivity.
|Commitee:||Hernando-Monge, Eva, Logan, Susan, Smith, Susan|
|School:||New York University|
|Department:||Basic Medical Science|
|School Location:||United States -- New York|
|Source:||DAI-B 74/07(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Cellular biology, Oncology|
|Keywords:||Cell cycle, Chromatin, Senescence, Sin3b, Tumor suppression|
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