SEQUENCE CONTEXT DEPENDENT EXCISION AND MUTAGENESIS

序列上下文相关(SCD)效应参与了突变过程，并定义了肿瘤中的突变热点，但除了突变结果外，人们对这种效应知之甚少。这项提案中的实验将严格检查SCD在切除和突变中的影响，这将有助于突变热点。最初，我们将建立DNA糖基酶切除的SCD规则。一旦规则被阐明，我们关于控制DNA糖基酶SCD切除规则的物理化学因素的假设将塑造实验设计。最后，通过改变与一个独特病变相邻的序列，我们将评估SCD对突变的影响。提出的研究将回答重要的生物学问题，涉及影响突变的因素、肿瘤突变数据库的质量以及可能导致癌症的特定碱基的变异性。

Sequence context dependent (SCD) effects are involved in the process of mutagenesis and define mutational hotspots in tumors, but little is known about such effects, except as mutational outcomes. The experiments in this proposal will rigorously examine SCD effects in excision and mutagenesis that would contribute to mutational hotspots. Initially, we will establish SCD rules for DNA glycosylase excision. Once the rules are elucidated, our hypotheses regarding the physical-chemical factors governing SCD excision rules for DNA glycosylases will mold the experimental design. Finally, by varying the sequence contiguous to a unique lesion, we will evaluate the role of SCD effects on mutagenesis. The studies proposed will answer important biological questions concerning factors influencing mutation, the quality of mutation databases for tumors, and the mutability of a particular base that could lead to cancer.