PUMA facilitates EMI 1-promoted cytoplasmic Rad51 ubiquitination and inhibits DNA repair in stem and progenitor cells  

作　　者：Jin Wook Kang Zhiyan Zhan Guangzhen Ji Youzhou Sang Daohong Zhou Yanxin Li Haizhong Feng Tao Cheng 

机构地区：[1]State Key Laboratory of Experimental Hematology,Institute of Hematology&Blood Diseases Hospital,Center for Stem Cell Medicine,Chinese Academy of Medical Sciences and Peking Union Medical College,Tianjin,China [2]Key Laboratory of Pediatric Hematology and Oncology Ministry of Health,Department of Hematology&Oncology,Shanghai Children's Medical Center,Shanghai Jiao Tong University School of medicine,Shanghai,China [3]Renji-Med X Clinical Stem Cell Research Center,Ren Ji Hospital,Shanghai Cancer Institute,School of Medicine,Shanghai Jiao Tong University,Shanghai,China [4]Department of Pharmacodynamics,College of Pharmacy,University of Florida at Gainesville,Gainesville,FL,USA

出　　处：《Signal Transduction and Targeted Therapy》2021年第4期1377-1387,共11页信号转导与靶向治疗（英文）

基　　金：This work was supported by the grants from the Ministry of Science and Technology of China(2016YFA0100600);the National Natural Science Foundation of China(81730006,81890990,81874078,82072896,81972341,and 81772663);CAMS Initiative for Innovative Medicine(2016-I2M-1-017,2019-I2M-1-006);Shanghai Municipal Science and Technology Commission(19JC1413500);Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant(No.20161310).

摘　　要：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 doublestrand 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.

关 键 词：PROGENITOR PUMA repair 

分 类 号：R329.2[医药卫生—人体解剖和组织胚胎学]