SEQUENCE CONTEXT DEPENDENT EXCISION AND MUTAGENESIS

序列背景依赖性（SCD）效应参与突变过程并定义肿瘤中的突变热点，但除了突变结果外，人们对此类效应知之甚少。本提案中的实验将严格检查 SCD 在切除和诱变中的影响，这可能会导致突变热点。首先，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 糖基化酶 SCD 切除规则的物理化学因素的假设将塑造实验设计。最后，通过改变与独特病变相邻的序列，我们将评估 SCD 效应对诱变的作用。拟议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.