University of Kansas Medical Center, Department of Pathology and Laboratory Medicine, Kansas City, Kansas, USA.
PLoS One. 2012;7(8):e42226. doi: 10.1371/journal.pone.0042226. Epub 2012 Aug 20.
Appropriate responses to damaged DNA are indispensible for preserving genome stability and preventing cancer. Tumor viruses often target DNA repair machinery to achieve transformation. The Human T-cell leukemia virus type I (HTLV-I) is the only known transforming human retrovirus and the etiological agent of Adult T-cell Leukemia (ATLL). Although HTLV-I-transformed leukemic cells have numerous genetic lesions, the precise role of the viral tax gene in this process is not fully understood.
Our results show a novel function of HTLV-I oncoprotein Tax as an inducer of genomic DNA double strand breaks (DDSB) during DNA replication. We also found that Tax acts as a potent inhibitor of homologous recombination (HR) DNA repair through the activation of the NF-kB pathway. These results were confirmed using HTLV-I molecular clones expressing Tax at physiological levels in a natural context. We further found that HTLV-I- and Tax-transformed cells are not more susceptible to DNA damaging agents and repair DNA lesions at a rate similar to that of normal cells. Finally, we demonstrated that during S phase, Tax-associated DDSB are preferentially repaired using the error-prone non-homologous end joining (NHEJ) pathway.
This study provides new insights in Tax effects on DNA repair and genome instability. Although it may not be self sufficient, the creation of DNA breaks and subsequent abnormal use of the non-conservative NHEJ DNA repair during the S phase in HTLV-I-infected Tax-expressing cells may cooperate with other factors to increase genetic and genome instability and favor transformation.
适当的 DNA 损伤反应对于维持基因组稳定性和预防癌症至关重要。肿瘤病毒常常靶向 DNA 修复机制以实现转化。人类 T 细胞白血病病毒 I 型（HTLV-I）是唯一已知的可转化人类逆转录病毒，也是成人 T 细胞白血病（ATLL）的病原体。尽管 HTLV-I 转化的白血病细胞存在多种遗传病变，但病毒 tax 基因在这一过程中的确切作用尚未完全阐明。
我们的研究结果表明，HTLV-I 癌蛋白 Tax 具有一种新的功能，即在 DNA 复制过程中诱导基因组 DNA 双链断裂（DDSB）。我们还发现 Tax 通过激活 NF-κB 通路，充当同源重组（HR）DNA 修复的有效抑制剂。这些结果通过在自然背景下以生理水平表达 Tax 的 HTLV-I 分子克隆得到证实。我们进一步发现，HTLV-I 和 Tax 转化的细胞对 DNA 损伤剂的敏感性没有增加，并且以与正常细胞相似的速度修复 DNA 损伤。最后，我们证明在 S 期，Tax 相关的 DDSB 优先通过易错的非同源末端连接（NHEJ）途径进行修复。
本研究为 Tax 对 DNA 修复和基因组不稳定性的影响提供了新的见解。尽管 Tax 可能不是完全自主的，但在 HTLV-I 感染的 Tax 表达细胞中，S 期 DSB 的形成和随后非保守 NHEJ DNA 修复的异常使用，可能与其他因素一起增加遗传和基因组不稳定性，从而促进转化。
