DNAH2 facilitates the homologous recombination repair of Fanconi anemia pathway through modulating FANCD2 ubiquitination  

作　　者：Lixian Chang Xingjie Gao Yuxia Wang Chunmin Huang Min Gao Xiaomin Wang Chao Liu Wenqi Wu Wenbin An Yang Wan Aoli Zhang Yingchi Zhang Weiping Yuan Xiaofan Zhu 

机构地区：[1]State Key Laboratory of Experimental Hematology,National Clinical Research Center for Blood Diseases,Institute of Hematology&Blood Diseases Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Tianjin,China [2]Department of Biochemistry and Molecular Biology,School of Basic Medical Sciences,Tianjin Medical University,Tianjin,China [3]Department of Hematology,Myelodysplastic Syndromes Diagnosis and Therapy Center,the First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,China [4]Beijing Institute of Genomics,Chinese Academy of Sciences(China National Center for Bioinformation),Beijing,China

出　　处：《Blood Science》2021年第3期71-77,共7页血液科学（英文）

基　　金：This work was partially supported by the National Key Research and Development Program of China(2016YFC0901503,2018YFA0107801);the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences,CIFMS(2017-I2M-3-015);the National Natural Science Foundation of China(81500156,81170470,81970149);and Tianjin Natural Science Foundation Project(20JCYBJC00470).

摘　　要：Fanconi anemia(FA),an X-linked genetic or autosomal recessive disease,exhibits complicated pathogenesis.Previously,we detected the mutated Dynein Axonemal Heavy Chain 2(DNAH2)gene in 2 FA cases.Herein,we further investigated the potential association between DNAH2 and the homologous recombination repair pathway of FA.The assays of homologous recombination repair,mitomycin C(MMC)sensitivity,immunofluorescence,and ubiquitination modification were performed in U2OS and DR-U2OS cell lines.In MMC-treated U2OS cells,the downregulation of the DNAH2 gene increased the sensitivity of cells to DNA inter-strand crosslinks.We also observed the reduced enrichment of FANCD2 protein to DNA damage sites.Furthermore,the ubiquitination modification level of FANCD2 was influenced by the deficiency of DNAH2.Thus,our results suggest that DNAH2 may modulate the cell homologous recombination repair partially by increasing the ubiquitination and the enrichment to DNA damage sites of FANCD2.DNAH2 may act as a novel co-pathogenic gene of FA patients.

关 键 词：DNAH2 FANCD2 Fanconi anemia Homologous recombination UBIQUITINATION 

分 类 号：R73[医药卫生—肿瘤]