Environmentally-modulated cytosine deamination in genome instability and cancer

胞苷脱氨为脱氧尿苷是生殖细胞和癌细胞突变的主要来源。 碱基切除和错配修复途径去除双链DNA中的脱氧尿苷。然而， 这种损伤通常发生在复制、转录和复制后形成的单链(Ss)dna中。 暴露在DNA损伤剂中。哺乳动物细胞也表达AID/APOBEC家族酶 在单链DNA中催化胞苷脱氨，其异常活性与癌症的发生有关。喜欢 他们针对的单链DNA，APOBEC酶的表达是由各种环境因素诱导的 提示这些暴露可能通过增加APOBEC在癌症的发生中起重要作用 酶和底物水平。APOBEC胞苷脱氨酶对核DNA的损伤程度，其 与环境DNA损伤剂的潜在协同作用以及脱氨基诱导的贡献 突变对癌症病因学的影响尚不清楚。同样不清楚的是去氨基胞苷是如何在 单链DNA。这项建议的目的是描述胞苷脱氨反应的机制和来源。 突变及其对环境致癌的可能贡献。Aim我将解决如果 人类癌症中APOBEC诱导的突变数量与临床疾病指标相关 进展和预后。通过APOBEC诱导的突变改变癌症相关基因也将 要下定决心。AIM II将确定单链DNA中脱氧尿苷向碱基位置的转换如何影响 突变和异位重组。将测量脱氨基诱导的突变和重组 在缺乏损伤耐受性机制的酵母中，这些途径在突变和 避免移位。AIM III将研究载脂蛋白BECs对人类染色体的诱变能力 细胞系模型中的DNA。导致单链DNA形成和/或APOBEC的影响环境暴露 表达式将会被处理。全基因组测序将被用来识别有风险的基因组特征。 APOBEC介导的突变。这些目标将提供对细胞和环境的理解 胞苷脱氨基诱导突变的机制及其致癌作用。

Cytidine deamination to deoxyuridine is a major source of mutation in both the germ-line and cancer cells. Base excision and mismatch repair pathways remove deoxyuridine from double stranded DNA. However, this lesion occurs commonly in single-strand (ss) DNA formed during replication, transcription, and after exposure to DNA damaging agents. Mammalian cells also express the AID/APOBEC family of enzymes that catalyze cytidine deamination in ssDNA and whose aberrant activity has been linked to carcinogenesis. Like the ssDNA they target, expression of APOBEC enzymes is induced by a variety of environmental agents suggesting these exposures may have an important role in carcinogenesis by increasing both APOBEC enzyme and substrate levels. The extent to which APOBEC cytidine deaminases damage nuclear DNA, their potential synergism with environmental DNA damaging agents, and the contribution of deamination-induced mutation to cancer etiology are unknown. Also unclear is how deaminated cytidines are processed within ssDNA. The goal of this proposal is to characterize mechanisms and sources of cytidine deamination-induced mutation and their possible contribution to environmentally-induced cancer. AIM I will address if the number of APOBEC-induced mutations in human cancers correlates with clinical measures of disease progression and prognosis. The alteration of cancer-related genes by APOBEC-induced mutations will also be determined. AIM II will determine how conversion of deoxyuridine to abasics sites in ssDNA impacts mutagenesis and ectopic recombination. Deamination-induced mutation and recombination will be measured in yeast lacking damage tolerance mechanisms to access these pathways' roles in mutation and translocation avoidance. AIM III will address the mutagenic capacity of APOBECs on human chromosomal DNA in a cell line model. The impact environmental exposures that induce ssDNA formation and/or APOBEC expression will be addressed. Whole genome sequencing will be used to identify genome features "at risk" of APOBEC-mediated mutation. These aims will provide an understanding of cellular and environmental mechanisms governing cytidine deamination-induced mutation and their contribution to carcinogenesis.