Function of REV3L in limiting oncogenesis via DNA damage tolerance

描述（由申请人提供）：REV 3L是pol 6的DNA聚合酶亚基，pol 6是一种参与基因组损伤耐受性的酶。REV 3L对胚胎发育至关重要，其原因仍有待澄清。我们发现Rev 3L缺陷的哺乳动物细胞具有高比率的自发染色体不稳定性，这也是许多癌症的特征。PI的实验室已经开发了条件性pol zeta-无效小鼠，并且似乎在这样的小鼠中的肿瘤的子集优先地是Rev 3L-无效的。因此，Pol 6可能是作为肿瘤抑制基因的专门DNA聚合酶的一个例子。拟议的实验将使用细胞，遗传和小鼠模型方法的新组合来测试REV 3L保护细胞免受内源性DNA损伤应激和染色体不稳定性的程度，并研究在没有REV 3L的情况下肿瘤发展的过程。目的是（1）检验REV 3L使细胞能够耐受DNA损伤的假设，DNA损伤可以破坏染色体完整性并干扰细胞增殖;（2）确定REV 3L蛋白的哪些结构域是正常细胞增殖和基因组稳定性所必需的;（3）测试小鼠中REV 3L功能丧失是否促进肿瘤发展。公共卫生相关性：DNA破坏剂产生突变，影响人类健康，衰老和基因组不稳定性。我们的研究表明，人类DNA修复蛋白REV 3L通过帮助防止基因组不稳定性来抑制肿瘤形成。了解肿瘤的REV 3L状态可能有助于定制治疗，并且可以预期对REV 3L功能的特异性干扰会影响肿瘤的发展。

DESCRIPTION (provided by applicant): REV3L is the DNA polymerase subunit of pol 6, an enzyme involved in tolerance of genomic damage. REV3L is essential for embryonic development, for reasons that remain to be clarified. We find that Rev3L-defective mammalian cells have high rates of spontaneous chromosome instability, a feature that is also characteristic of many cancers. The PI's laboratory has developed a conditional pol zeta-null mouse, and it appears that a subset of tumors in such mice are preferentially Rev3L-null. Pol 6 may thus be an example of a specialized DNA polymerase that acts as a tumor suppressor gene. The proposed experiments will use a new combination of cellular, genetic, and mouse model approaches to test the extent to which REV3L protects cells against endogenous DNA-damaging stress and chromosomal instability, and to investigate the process of tumor development in the absence of REV3L. The aims are (1) to test the hypothesis that REV3L enables cells to tolerate DNA damage that can disrupt chromosome integrity and interfere with cell proliferation; (2) to determine which domains of the REV3L protein are necessary for normal cell proliferation and genome stability; (3) to test whether loss of REV3L function in mice promotes tumor development. PUBLIC HEALTH RELEVANCE: DNA damaging agents produce mutations that affect human health, aging, and genome instability. Our research suggests that the human DNA repair protein REV3L suppresses tumor formation by helping to prevent genome instability. Knowledge of the REV3L status of tumors could be useful in tailoring therapies, and specific interference with REV3L function could be expected to influence tumor development.