Genome-wide analysis of the formation and mutagenesis of atypical UV photoproducts in skin cancer

皮肤癌中非典型紫外线光产物的形成和诱变的全基因组分析

基本信息

  • 批准号:
    10557820
  • 负责人:
  • 金额:
    $ 41.69万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-04-01 至 2026-01-31
  • 项目状态:
    未结题

项目摘要

Abstract: Exposure to solar ultraviolet (UV) light creates DNA damage that induces high levels of somatic mutations in human skin cancers like melanoma. UV light most commonly causes cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) at dipyrimidine sequences (i.e., TT, TC, CT, and CC). Deamination of cytidines in these lesions or mutagenic bypass leads to their frequent conversion to mutations. As a result, UV- exposed cells and skin cancers are dominated by C to T and CC to TT substitutions in dipyrimidine sequences that collectively constitute a UV mutation signature. Surprisingly, many driver mutations that contribute to melanoma progression have sequence context and substitution characteristics that do not conform to the canonical UV mutation signature. For example, the most common melanoma driver mutation, BRAF V600E, involves a T to A substitution in a GTG sequence context. This difference in mutation characteristics between most UV-induced mutations and melanoma driver mutations has led to the hypothesis that UV light induces melanomagenesis by mechanisms other than the induction of mutations. However, we have recently provided experimental evidence of mutations caused by rare, non-canonical UV lesions in whole genome sequenced yeast and bioinformatics evidence of similar lesions in human clinical skin cancers. These lesions are likely bulky photoproducts formed at TA, CA, and AC dinucleotides. Strikingly, the mutations associated with these atypical UV photoproducts have identical characteristics to many recurrent driver mutations in melanoma, suggesting that these rare lesions may play a significant role in causing skin cancer. The objective of this proposal is to better define the characteristics of atypical UV photoproducts and their contribution to cancer progression. In Aim I, we will utilize CPD and 6-4PP photolyases expressed in yeast to assign UV-induced mutation classes to their corresponding lesion types as well as assess the ability of physiological UVB light to induce mutation classes associated with atypical UV photoproducts in yeast and human cells. In Aim II, we will analyze the genome-wide distribution of atypical TA photoproducts using a novel high throughput sequencing method, called UVDE-seq. We will also characterize the formation of putative CA and AC photoproducts and their contribution to oncogenic BRAF mutations. Finally, Aim III will identify DNA polymerases involved in the error-free and error-prone bypass of TA and AC photoproducts. Successful completion of these aims will provide new insights into the molecular causes of skin cancer, and thereby define a new paradigm of UV mutagenesis that could potentially explain the epidemiological association of acute UV exposure with increased melanoma incidence.
文摘:

项目成果

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STEVEN A ROBERTS其他文献

STEVEN A ROBERTS的其他文献

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{{ truncateString('STEVEN A ROBERTS', 18)}}的其他基金

Regulation of APOBEC3 cytidine deaminase-induced mutation during cancer development
癌症发展过程中 APOBEC3 胞苷脱氨酶诱导突变的调控
  • 批准号:
    10583753
  • 财政年份:
    2023
  • 资助金额:
    $ 41.69万
  • 项目类别:
Regulation of APOBEC3 cytidine deaminase-induced mutation during cancerdevelopment
癌症发展过程中 APOBEC3 胞苷脱氨酶诱导突变的调控
  • 批准号:
    10880034
  • 财政年份:
    2023
  • 资助金额:
    $ 41.69万
  • 项目类别:
Characterizing the contribution of transcription-associated DNA-topoisomerase adducts to mutagenesis in cancer
表征转录相关 DNA 拓扑异构酶加合物对癌症诱变的贡献
  • 批准号:
    10887019
  • 财政年份:
    2022
  • 资助金额:
    $ 41.69万
  • 项目类别:
Characterizing the contribution of transcription-associated DNA-topoisomerase adducts to mutagenesis in cancer
表征转录相关 DNA 拓扑异构酶加合物对癌症诱变的贡献
  • 批准号:
    10670192
  • 财政年份:
    2022
  • 资助金额:
    $ 41.69万
  • 项目类别:
Characterizing the contribution of transcription-associated DNA-topoisomerase adducts to mutagenesis in cancer
表征转录相关 DNA 拓扑异构酶加合物对癌症诱变的贡献
  • 批准号:
    10444838
  • 财政年份:
    2022
  • 资助金额:
    $ 41.69万
  • 项目类别:
Genome-wide analysis of the formation and mutagenesis of atypical UV photoproducts in skin cancer
皮肤癌中非典型紫外线光产物的形成和诱变的全基因组分析
  • 批准号:
    10378633
  • 财政年份:
    2021
  • 资助金额:
    $ 41.69万
  • 项目类别:
Genome-wide analysis of the formation and mutagenesis of atypical UV photoproducts in skin cancer
皮肤癌中非典型紫外线光产物的形成和诱变的全基因组分析
  • 批准号:
    10179949
  • 财政年份:
    2021
  • 资助金额:
    $ 41.69万
  • 项目类别:
Mechanisms of genome instability induced by APOBEC Cytidine Deaminases and its impacts during cancer development.
APOBEC 胞苷脱氨酶诱导的基因组不稳定机制及其在癌症发展过程中的影响。
  • 批准号:
    9919517
  • 财政年份:
    2017
  • 资助金额:
    $ 41.69万
  • 项目类别:
Mechanisms of genome instability induced by APOBEC Cytidine Deaminases and its impacts during cancer development.
APOBEC 胞苷脱氨酶诱导的基因组不稳定机制及其在癌症发展过程中的影响。
  • 批准号:
    9919034
  • 财政年份:
    2017
  • 资助金额:
    $ 41.69万
  • 项目类别:
Mechanisms of genome instability induced by APOBEC Cytidine Deaminases and its impacts during cancer development.
APOBEC 胞苷脱氨酶诱导的基因组不稳定机制及其在癌症发展过程中的影响。
  • 批准号:
    9363653
  • 财政年份:
    2017
  • 资助金额:
    $ 41.69万
  • 项目类别:

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腺嘌呤核苷酸转位酶在慢性阻塞性肺病(COPD)线粒体功能相关衰老中的作用
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使用 FRET 开发 miRNA 和腺嘌呤甲基转移酶的诺贝尔检测方法
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胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
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胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
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  • 财政年份:
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胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
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