UHRF1 depletion causes a G2/M arrest, activation of DNA damage response and apoptosis.
UHRF1 depletion causes a G2/M arrest, activation of DNA damage response and apoptosis.
复制标题
DOI：
10.1042/bj20100840
复制
发表时间：
2011-04-01
期刊：
影响因子：
--
通讯作者：
Ukomadu C
中科院分区：
文献类型：
--
作者：
Tien AL;Senbanerjee S;Kulkarni A;Mudbhary R;Goudreau B;Ganesan S;Sadler KC;Ukomadu C
泛素样蛋白（Ubiquitin-like protein，UHRF 1）是一种含有PHD和RING finger domain-1的蛋白质，在细胞周期和表观遗传调控中起重要作用。在这项研究中，我们表明，消耗癌细胞的UHRF 1导致激活的DNA损伤反应途径，细胞周期停滞在G2/M和凋亡依赖于caspase-8。在去除UHRF 1的细胞中的DNA损伤反应通过以下来说明：组蛋白H2 AX在丝氨酸139上的磷酸化、CHK 2在苏氨酸68上的磷酸化、CDC 25在丝氨酸216上的磷酸化和CDK 1在酪氨酸15上的磷酸化。此外，我们发现UHRF 1在DNA损伤位点积累，这表明UHRF 1缺失细胞中的细胞周期阻滞是由于在损伤修复中的重要作用。UHRF 1耗竭的结果是细胞凋亡：细胞经历半胱天冬酶8和3的活化，半胱天冬酶-8的耗竭防止由UHRF 1敲低诱导的细胞死亡。有趣的是，细胞周期阻滞和凋亡发生在p53含有和缺陷的细胞中。从这些研究中，我们得出结论，UHRF 1链接表观遗传调控与DNA复制。
Ubiquitin-like protein, containing PHD and RING finger domains-1 (UHRF1) is required for cell cycle progression and epigenetic regulation. In this study, we show that depleting cancer cells of UHRF1 causes activation of the DNA damage response pathway, cell cycle arrest in G2/M and apoptosis dependent on caspase-8. The DNA damage response in cells depleted of UHRF1 is illustrated by: phosphorylation of histone H2AX on serine 139, phosphorylation of CHK2 on threonine 68, phosphorylation of CDC25 on serine 216 and phosphorylation of CDK1 on tyrosine 15. Moreover, we find that UHRF1 accumulates at sites of DNA damage suggesting that the cell cycle block in UHRF1 depleted cells is due to an important role in damage repair. The consequence of UHRF1 depletion is apoptosis: cells undergo activation of caspases 8 and 3 and depletion of caspase-8 prevents cell death induced by UHRF1 knock-down. Interestingly, the cell cycle block and apoptosis occurs in p53 containing and deficient cells. From these studies we conclude that UHRF1 links epigenetic regulation with DNA replication.