PUMA facilitates EMI1-promoted cytoplasmic Rad51 ubiquitination and inhibits DNA repair in stem and progenitor cells.
PUMA facilitates EMI1-promoted cytoplasmic Rad51 ubiquitination and inhibits DNA repair in stem and progenitor cells.
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PUMA 促进 EMI1 促进的细胞质 Rad51 泛素化并抑制干细胞和祖细胞中的 DNA 修复
DOI：
10.1038/s41392-021-00510-w
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发表时间：
2021-03-31
影响因子：
39.3
通讯作者：
Cheng T
中科院分区：
文献类型：
--
作者：
Kang JW;Zhan Z;Ji G;Sang Y;Zhou D;Li Y;Feng H;Cheng T
通过干细胞和祖细胞中适当的DNA修复来维持遗传稳定性对于组织修复和再生是必不可少的，同时防止损伤后的细胞转化。在暴露于致死剂量的电离辐射（IR）后，CD4A的缺失显著增加了小鼠的存活率，而不会促进长期存活者的肿瘤发生。这一发现表明，p53上调的细胞凋亡调节因子（p53）可能具有调节细胞凋亡以外的功能。在这里，我们确定了一种新的作用，PUMA在调控DNA修复胚胎或诱导多能干细胞（PSC）和永生化造血祖细胞（HPC）后IR。我们发现，PUMA缺陷的PSC和HPC表现出显着较高的双链断裂（DSB）DNA修复活性通过Rad51介导的同源重组（HR）。这是因为BRA可以与细胞质中的早期有丝分裂抑制因子1（EMI1）和Rad51结合，以促进EMI1介导的细胞质Rad51泛素化和降解，从而抑制Rad51核转位和HR DNA修复。我们的数据表明，DSB DNA修复的阻遏物，从而提供了一个新的理论基础，在再生细胞中的DNA损伤的背景下，治疗靶向DSB A。
Maintenance of genetic stability via proper DNA repair in stem and progenitor cells is essential for the tissue repair and regeneration, while preventing cell transformation after damage. Loss of PUMA dramatically increases the survival of mice after exposure to a lethal dose of ionizing radiation (IR), while without promoting tumorigenesis in the long-term survivors. This finding suggests that PUMA (p53 upregulated modulator of apoptosis) may have a function other than regulates apoptosis. Here, we identify a novel role of PUMA in regulation of DNA repair in embryonic or induced pluripotent stem cells (PSCs) and immortalized hematopoietic progenitor cells (HPCs) after IR. We found that PUMA-deficient PSCs and HPCs exhibited a significant higher double-strand break (DSB) DNA repair activity via Rad51-mediated homologous recombination (HR). This is because PUMA can be associated with early mitotic inhibitor 1 (EMI1) and Rad51 in the cytoplasm to facilitate EMI1-mediated cytoplasmic Rad51 ubiquitination and degradation, thereby inhibiting Rad51 nuclear translocation and HR DNA repair. Our data demonstrate that PUMA acts as a repressor for DSB DNA repair and thus offers a new rationale for therapeutic targeting of PUMA in regenerative cells in the context of DNA damage.
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影响因子：
19
作者：
Ceccaldi R;Rondinelli B;D'Andrea AD
通讯作者：
D'Andrea AD
影响因子：
1.6
作者：
Dickey JS;Redon CE;Nakamura AJ;Baird BJ;Sedelnikova OA;Bonner WM
通讯作者：
Bonner WM
影响因子：
16
作者：
Davies, AA;Masson, JY;West, SC
通讯作者：
West, SC
p53-PUMA轴抑制了IPSC的生成。
影响因子：
16.6
作者：
Li, Yanxin;Feng, Haizhong;Gu, Haihui;Lewis, Dale W.;Yuan, Youzhong;Zhang, Lei;Yu, Hui;Zhang, Peng;Cheng, Haizi;Miao, Weimin;Yuan, Weiping;Cheng, Shi-Yuan;Gollin, Susanne M.;Cheng, Tao
通讯作者：
Cheng, Tao
影响因子：
2.8
作者：
Hamasaki, Kanya;Imai, Kazue;Kusunoki, Yoichiro
通讯作者：
Kusunoki, Yoichiro