SEQUENCE CONTEXT DEPENDENT EXCISION AND MUTAGENESIS

序列上下文依赖（SCD）效应参与诱变过程并定义肿瘤中的突变热点，但除了作为突变结果外，对此类效应知之甚少。本提案中的实验将严格检查SCD在切除和诱变中的作用，这将有助于突变热点。首先，我们将建立DNA糖基化酶切除的SCD规则。一旦规则阐明，我们的假设有关的物理-化学因素的SCD切除规则的DNA糖基化酶将塑造实验设计。最后，通过改变一个独特的病变的序列，我们将评估SCD的诱变效应的作用。这些研究将回答重要的生物学问题，包括影响突变的因素、肿瘤突变数据库的质量以及可能导致癌症的特定碱基的突变性。

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.