The KRAB Zinc Finger Protein Roma/Zfp157 Is a Critical Regulator of Cell-Cycle Progression and Genomic Stability.
The KRAB Zinc Finger Protein Roma/Zfp157 Is a Critical Regulator of Cell-Cycle Progression and Genomic Stability.
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DOI：
10.1016/j.celrep.2016.03.078
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发表时间：
2016-04-26
期刊：
影响因子：
8.8
通讯作者：
Watson CJ
中科院分区：
文献类型：
--
作者：
Ho TLF;Guilbaud G;Blow JJ;Sale JE;Watson CJ
DNA复制和细胞分裂的调控对组织生长和基因组完整性的维持至关重要，在乳腺等持续再生的组织中尤为重要。我们之前的研究表明，krab结构域锌指蛋白Roma/Zfp157的破坏会导致妊娠期间乳腺上皮细胞（MECs）的过度增殖。在这里，我们描述了罗马产生这种表型的机制。mec中Roma的消融会导致计划外增殖、复制应激、DNA损伤和基因组不稳定。此外，小鼠胚胎成纤维细胞（mef）的Roma缺失表现出p21Cip1和双联蛋白的下调，并加速了复制叉的速度，这伴随着有丝分裂错误和多倍体的高发生率。相反，mec中Roma的过表达会阻止细胞周期的进展，而sirna介导的p21Cip1敲低在一定程度上改善了这种表型。因此，Roma是细胞周期的重要调节因子，是维持基因组稳定性所必需的。KRAB结构域锌指蛋白Roma/Zfp157调控增殖Roma调控细胞周期调控因子p21Cip1和geminin Roma的表达调控复制叉动力学和基因组稳定性小鼠胚胎成纤维细胞中Roma的切除导致内重复Ho等人证明转录调控因子Roma， KRAB/锌指蛋白家族的成员，控制细胞周期进程和复制叉速度。泌乳乳腺中Roma的缺失导致复制应激和DNA损伤信号通路的激活。
Regulation of DNA replication and cell division is essential for tissue growth and maintenance of genomic integrity and is particularly important in tissues that undergo continuous regeneration such as mammary glands. We have previously shown that disruption of the KRAB-domain zinc finger protein Roma/Zfp157 results in hyperproliferation of mammary epithelial cells (MECs) during pregnancy. Here, we delineate the mechanism by which Roma engenders this phenotype. Ablation of Roma in MECs leads to unscheduled proliferation, replication stress, DNA damage, and genomic instability. Furthermore, mouse embryonic fibroblasts (MEFs) depleted for Roma exhibit downregulation of p21Cip1 and geminin and have accelerated replication fork velocities, which is accompanied by a high rate of mitotic errors and polyploidy. In contrast, overexpression of Roma in MECs halts cell-cycle progression, whereas siRNA-mediated p21Cip1 knockdown ameliorates, in part, this phenotype. Thus, Roma is an essential regulator of the cell cycle and is required to maintain genomic stability. The KRAB-domain zinc finger protein Roma/Zfp157 regulates proliferation Roma regulates expression of the cell-cycle regulators p21Cip1 and geminin Roma regulates replication fork dynamics and genomic stability Ablation of Roma in mouse embryonic fibroblasts leads to endoreduplication Ho et al. demonstrate that the transcriptional regulator Roma, a member of the KRAB/Zinc finger protein family, controls cell-cycle progression and replication fork velocity. Loss of Roma in lactating mammary gland results in replication stress and activation of DNA damage signaling pathways.