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性和外源性来源的DNA损伤的威胁。 然而，突变，这是遗传序列的变化，在DNA，也可以出现的结果， 在复制未受损DNA过程中出现的错误。最近，一个全新的错误家族- 已经发现了DNA聚合酶。在生命的所有三个领域中， 聚合酶是有益的，因为它们可以复制过去的DNA损伤，但它们也 这可能是有害的，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，它们可能是突变的潜在来源。 会导致遗传疾病比如癌症这项研究的假设是 细胞能够并且必须控制它们的易错DNA聚合酶的活动。为了验证这一 假设，控制E.卷曲易错DNA聚合酶IV 会被发现并被定性。具体目标是：（1）确定新的调节因素， 影响Pol IV的致突变活性;（2）表征调节Pol IV的蛋白质和途径 IV水平或活性;和，（3）进一步表征已经确定的调节因素。 由于Pol IV是真核易错DNA聚合酶的密切同源物，因此， 包括人类在内的生物体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. coil's 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.