Chang Lixian, Gao Xingjie, Wang Yuxia, Huang Chunmin, Gao Min, Wang Xiaomin, Liu Chao, Wu Wenqi, An Wenbin, Wan Yang, Zhang Aoli, Zhang Yingchi, Yuan Weiping, Zhu Xiaofan
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.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Blood Sci. 2021 Jun 7;3(3):71-77. doi: 10.1097/BS9.0000000000000076. eCollection 2021 Jul.
Fanconi anemia (FA), an X-linked genetic or autosomal recessive disease, exhibits complicated pathogenesis. Previously, we detected the mutated Dynein Axonemal Heavy Chain 2 () 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 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 may modulate the cell homologous recombination repair partially by increasing the ubiquitination and the enrichment to DNA damage sites of FANCD2. may act as a novel co-pathogenic gene of FA patients.
范可尼贫血（FA）是一种X连锁隐性或常染色体隐性遗传病，其发病机制复杂。此前，我们在2例FA患者中检测到动力蛋白轴丝重链2（DNAH2）基因发生突变。在此，我们进一步研究了DNAH2与FA同源重组修复途径之间的潜在关联。在U2OS和DR-U2OS细胞系中进行了同源重组修复、丝裂霉素C（MMC）敏感性、免疫荧光和泛素化修饰检测。在经MMC处理的U2OS细胞中，DNAH2基因的下调增加了细胞对DNA链间交联的敏感性。我们还观察到FANCD2蛋白在DNA损伤位点的富集减少。此外，FANCD2的泛素化修饰水平受DNAH2缺乏的影响。因此，我们的结果表明，DNAH2可能通过增加FANCD2的泛素化及其在DNA损伤位点的富集来部分调节细胞同源重组修复。DNAH2可能是FA患者的一个新的共致病基因。
