Regulation of an Error-Prone Polymerase

基因组的稳定性对个体的健康和物种的保存至关重要。这种稳定性可能受到来自内源和外源的DNA损伤的威胁。然而，突变是DNA中可遗传的序列变化，也可能是复制未受损DNA过程中出错的结果。最近发现了一个全新的容易出错的DNA聚合酶家族。在生命的所有三个领域中都发现了这些聚合酶，它们是有益的，因为它们可以复制过去的DNA损伤，但它们也有潜在的有害作用，因为它们经常出错，即使在未受损的DNA上也是如此。如果这些聚合酶的活性不受控制，它们可能是导致癌症等遗传疾病的突变的一个有效来源。这项拟议研究的假设是，细胞能够而且必须控制它们容易出错的DNA聚合酶的活性。为了验证这一假设，将找到控制E.colts易错DNA聚合酶IV(POL IV)活性的途径并对其进行表征。具体目的是：(1)确定影响Pol IV诱变活性的新的调节因子；(2)确定调节Pol IV水平或活性的蛋白质和途径；以及(3)进一步确定已确定的调节因子的特征。由于POL IV是真核生物中容易出错的DNA聚合酶的紧密同源物，包括人类在内的高等生物可能会使用类似的控制机制。

Genomic stability is vital to the health of the individual and the preservation of the species. This stability can be threatened by DNA damage from endogenous and exogenous sources. However, mutations, which are heritable sequence changes in the DNA, can also arise as a result of errors made during replication of undamaged DNA. Recently an entirely new family of error-prone DNA polymerases has been discovered. Found in all three domains of life, these polymerases are beneficial because they can replicate past DNA lesions, but they are also potentially detrimental because they make frequent errors, even on undamaged DNA. If the activities of these polymerases are not controlled, they could be a potent source of the mutations that lead to genetic disorders such as cancer. The hypothesis underlying the proposed research is that cells can and must control the activities of their error-prone DNA polymerases. To test this hypothesis, pathways that control the activity of E. colts error-prone DNA polymerase IV (Pol IV) will be found and characterized. The specific aims are: (1) to identify new regulatory factors that affect the mutagenic activity of Pol IV; (2) to characterize the proteins and pathways regulating Pol IV levels or activity; and, (3) to further characterize the regulatory factors that are already identified. Because Pol IV is a close homologue of eukaryotic error-prone DNA polymerases, higher organisms, including humans, may use similar control mechanisms.