The mlNO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stability  

作　　者：Jin-Na Min Yanyan Tian Yang Xiao Ling Wu Lei Li Sandy Chang 

机构地区：[1]Department of Laboratory Medicine and Pathology, Yale University School of Medicine, New Haven, CT 06520, USA [2]Department of Experimental Radiation Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA: [3]Department ofGenetics, MD Anderson Cancer Center, Houston, TX 77030, USA

出　　处：《Cell Research》2013年第12期1396-1413,共18页细胞研究（英文版）

摘　　要：The INO80 （inositol requiring mutant 80） chromatin remodeling complex plays important roles in transcriptional regulation and DNA replication and repair, and consists of several functional protein subunits, including the critical Ino80 ATPase catalytic subunit. While the function of INO80 has been studied in yeast and mammalian cell lines, we do not know how mlno80 contributes to the maintenance of genome stability to prevent cancer development in mice. Here, we use a conditional knockout approach to explore the cellular and organismal functions of mlno80. Dele tion of mlno80 results in profound cellular proliferative defects and activation of p21-dependent cellular senescence. While mlno80 is required for efficient repair of DNA double strand breaks, its depletion did not impact upon the formation of y-H2AX and 53BP1 DNA damage foci, or the activation of the ATM-CHK2-dependent DNA damage response, mlno80 deletion inhibited the generation of single-strand DNA, resulting in defects in homology-directed DNA repair （HDR） at telomeres. Fragile telomeres were prominent in mlno80^△/△A MEFs, suggesting that chromatin remodeling is required for efficient telomere replication, mlno80^-/- mouse embryos die early during embryogenesis, while conditional deletion of mlno80 in adult mice results in weight loss and premature death. In a p53^-/- tumor prone background, mlno80 haploinsufficiency favored the development of sarcomas. Our studies suggest that the mIno80 chromatin remodeling complex plays important roles in telomere replication, HDR-mediated repair of dys functional telomeres, and maintenance of ~enome stability.The INO80 （inositol requiring mutant 80） chromatin remodeling complex plays important roles in transcriptional regulation and DNA replication and repair, and consists of several functional protein subunits, including the critical Ino80 ATPase catalytic subunit. While the function of INO80 has been studied in yeast and mammalian cell lines, we do not know how mlno80 contributes to the maintenance of genome stability to prevent cancer development in mice. Here, we use a conditional knockout approach to explore the cellular and organismal functions of mlno80. Dele tion of mlno80 results in profound cellular proliferative defects and activation of p21-dependent cellular senescence. While mlno80 is required for efficient repair of DNA double strand breaks, its depletion did not impact upon the formation of y-H2AX and 53BP1 DNA damage foci, or the activation of the ATM-CHK2-dependent DNA damage response, mlno80 deletion inhibited the generation of single-strand DNA, resulting in defects in homology-directed DNA repair （HDR） at telomeres. Fragile telomeres were prominent in mlno80^△/△A MEFs, suggesting that chromatin remodeling is required for efficient telomere replication, mlno80^-/- mouse embryos die early during embryogenesis, while conditional deletion of mlno80 in adult mice results in weight loss and premature death. In a p53^-/- tumor prone background, mlno80 haploinsufficiency favored the development of sarcomas. Our studies suggest that the mIno80 chromatin remodeling complex plays important roles in telomere replication, HDR-mediated repair of dys functional telomeres, and maintenance of ~enome stability.

关 键 词：DNA damage TELOMERE CANCER genome instability CHROMATIN REPLICATION 

分 类 号：Q343.2[生物学—遗传学] Q523