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内源性和外源性DNA损伤的威胁。然而，突变，即DNA中可遗传的序列变化，也可能由于未受损DNA复制过程中发生的错误而产生。最近发现了一个全新的易出错DNA聚合酶家族。这些聚合酶存在于生命的所有三个领域，它们是有益的，因为它们可以复制过去的DNA损伤，但它们也有潜在的危害，因为它们经常出错，即使是在未受损的DNA上。如果这些聚合酶的活性不受控制，它们可能是导致遗传疾病（如癌症）的突变的有力来源。这项研究提出的假设是，细胞能够而且必须控制它们容易出错的DNA聚合酶的活动。为了验证这一假设，控制大肠杆菌易出错DNA聚合酶IV （Pol IV）活性的途径将被发现并表征。具体目的是：(1)确定影响Pol IV致突变活性的新调控因子；(2)表征调节Pol IV水平或活性的蛋白质和途径；(3)进一步描述已经确定的调节因素。由于Pol IV是真核生物容易出错的DNA聚合酶的密切同源物，包括人类在内的高等生物可能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.