Hepatitis B virus X protein interferes with cellular DNA repair
Hepatitis B virus X protein interferes with cellular DNA repair
复制标题
DOI：
10.1128/jvi.72.1.266-272.1998
复制
发表时间：
1998-01-01
影响因子：
5.4
通讯作者：
Slagle, BL
中科院分区：
文献类型：
--
作者：
Becker, SA;Lee, TH;Slagle, BL
乙型肝炎病毒X蛋白（HBx）是一种广泛作用的反激活因子，与肝癌的发展有关。最近，有报道称HBx与几种不同的细胞蛋白相互作用，包括我们报道的它与XAP-1的结合，XAP-1是猿猴修复蛋白UVDDB的人类同源物。在本研究中，利用几个HBx突变体将HBx与XAP-1/UVDDB结合所需的最小结构域定位到氨基酸55至101上。XAP-1/UVDDB的正常功能被认为涉及与受损DNA的结合，这是核苷酸切除修复（NER）的第一步；因此，我们假设这种相互作用可能会影响细胞纠正基因组病变的能力。在两项测量NER（计划外DNA合成和宿主细胞再激活）的独立试验中，HBx的表达显著抑制了细胞修复受损DNA的能力。在实验条件下，HBx的表达水平与之前在自然病毒感染期间观察到的水平相似，并且能够反激活几个靶报告基因。这些结果与一个模型是一致的，在这个模型中，HBx通过阻止细胞有效地修复受损的DNA，从而导致DNA突变的积累，最终导致癌症，从而在肝癌的发生中起辅助因子的作用。对细胞DNA修复过程的不利影响表明，肿瘤相关病毒可能有助于致癌的新机制。
The hepatitis B virus X protein (HBx) is a broadly acting transactivator implicated in the development of liver cancer. Recently, HBx has been reported to interact with several different cellular proteins, including our report of its binding to XAP-1, the human homolog of the simian repair protein UVDDB. In the present study, several HBx mutants were used to localize the minimal domain of HBx required for binding to XAP-1/UVDDB to amino acids 55 to 101. The normal function of XAP-1/UVDDB is thought to involve binding to damaged DNA, the first step in nucleotide excision repair (NER); therefore, we hypothesized that this interaction may affect the cell's capacity to correct lesions in the genome. When tested in two independent assays that measure NER (unscheduled DNA synthesis and host cell reactivation), the expression of HBx significantly inhibited the ability of cells to repair damaged DNA. Under the assay conditions, HBx was expressed at a level similar to that previously observed during natural viral infection and was able to transactivate several target reporter genes. These results are consistent,vith a model in which HBx acts as a cofactor in hepatocarcinogenesis by preventing the cell from efficiently repairing damaged DNA, thus leading to an accumulation of DNA mutations and, eventually, cancer. An adverse effect on cellular DNA repair processes suggests a new mechanism by which a tumor-associated virus might contribute to carcinogenesis.