High UV damage and low repair, but not cytosine deamination, stimulate mutation hotspots at ETS binding sites in melanoma

• 成果类型: Article
• 署名作者: Duan, Mingrui; Song, Shenghan; Wasserman, Hana; Lee, Po-Hsuen; Liu, Ke Jian; Gordan, Raluca; He, Yi; Mao, Peng
• 署名单位: University of New Mexico; University of New Mexico; University of New Mexico; Duke University; State University of New York (SUNY) System; Stony Brook University; Duke University; Duke University; Duke University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9580
• DOI: 10.1073/pnas.2310854121
• 发表日期: 2024-01-23
• 关键词: nucleotide excision-repair; transcription factors; pyrimidine dimers; dna-polymerase; tert promoter; sequence; cancer; protein; bypass

摘要

Noncoding mutation hotspots have been identified in melanoma and many of them occur at the binding sites of E26 transformation-specific (ETS) proteins; however, their formation mechanism and functional impacts are not fully understood. Here, we used UV (Ultraviolet) damage sequencing data and analyzed cyclobutane pyrimidine dimer (CPD) formation, DNA repair, and CPD deamination in human cells at single-nucleotide resolution. Our data show prominent CPD hotspots immediately after UV irradiation at ETS binding sites, particularly at sites with a conserved TTCCGG motif, which correlate with mutation hotspots identified in cutaneous melanoma. Additionally, CPDs are repaired slower at ETS binding sites than in flanking DNA. Cytosine deamination in CPDs to uracil is suggested as an important step for UV mutagenesis. However, we found that CPD deamination is significantly suppressed at ETS binding sites, particularly for the CPD hotspot on the 5 ' side of the ETS motif, arguing against a role for CPD deamination in promoting ETS-associated UV mutations. Finally, we analyzed a subset of frequently mutated promoters, including the ribosomal protein genes RPL13A and RPS20, and found that mutations in the ETS motif can significantly reduce the promoter activity. Thus, our data identify high UV damage and low repair, but not CPD deamination, as the main mechanism for ETS-associated mutations in melanoma and uncover important roles of often-overlooked mutation hotspots in perturbing gene transcription.