Department of Environmental Health Science, College of Public Health, University of Georgia, Athens, GA 30602, USA.
Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
Nucleic Acids Res. 2024 Oct 28;52(19):11704-11719. doi: 10.1093/nar/gkae755.
Aflatoxin B1 (AFB1), a potent mycotoxin, is one of the environmental risk factors that cause liver cancer. In the liver, the bioactivated AFB1 intercalates into the DNA double helix to form a bulky DNA adduct which will lead to mutation if left unrepaired. Here, we adapted the tXR-seq method to measure the nucleotide excision repair of AFB1-induced DNA adducts at single-nucleotide resolution on a genome-wide scale, and compared it with repair data obtained from conventional UV-damage XR-seq. Our results showed that transcription-coupled repair plays a major role in the damage removal process. We further analyzed the distribution of nucleotide excision repair sites for AFB1-induced DNA adducts within the 3D human genome organization. Our analysis revealed a heterogeneous AFB1-dG repair across four different organization levels, including chromosome territories, A/B compartments, TADs, and chromatin loops. We found that chromosomes positioned closer to the nuclear center and regions within A compartments have higher levels of nucleotide excision repair. Notably, we observed high repair activity around both TAD boundaries and loop anchors. These findings provide insights into the complex interplay between AFB1-induced DNA damage repair, transcription, and 3D genome organization, shedding light on the mechanisms underlying AFB1-induced mutagenesis.
黄曲霉毒素 B1（AFB1）是一种强效的真菌毒素，是导致肝癌的环境风险因素之一。在肝脏中，生物活化的 AFB1 插入 DNA 双螺旋中，形成一个体积庞大的 DNA 加合物，如果不进行修复，就会导致突变。在这里，我们采用 tXR-seq 方法，以全基因组规模在单核苷酸分辨率上测量 AFB1 诱导的 DNA 加合物的核苷酸切除修复，将其与从常规 UV 损伤 XR-seq 获得的修复数据进行比较。我们的结果表明，转录偶联修复在损伤清除过程中起着主要作用。我们进一步分析了 3D 人类基因组结构中 AFB1 诱导的 DNA 加合物的核苷酸切除修复位点的分布。我们的分析揭示了在四个不同的组织水平上 AFB1-dG 修复的异质性，包括染色体区域、A/B 区室、TAD 和染色质环。我们发现，靠近核中心定位的染色体和 A 区室内部的区域具有更高水平的核苷酸切除修复。值得注意的是，我们在 TAD 边界和环锚点周围观察到了高修复活性。这些发现深入了解了 AFB1 诱导的 DNA 损伤修复、转录和 3D 基因组组织之间的复杂相互作用，揭示了 AFB1 诱导的突变机制。
