DNA base damage is an important contributor to genome instability, but how the formation and repair of these lesions is affected by the genomic landscape and contributes to mutagenesis is unknown. Here, we describe genome-wide maps of DNA base damage, repair, and mutagenesis at single nucleotide resolution in yeast treated with the alkylating agent methyl methanesulfonate (MMS). Analysis of these maps revealed that base excision repair (BER) of alkylation damage is significantly modulated by chromatin, with faster repair in nucleosome-depleted regions, and slower repair and higher mutation density within strongly positioned nucleosomes. Both the translational and rotational settings of lesions within nucleosomes significantly influence BER efficiency; moreover, this effect is asymmetric relative to the nucleosome dyad axis and is regulated by histone modifications. Our data also indicate that MMS-induced mutations at adenine nucleotides are significantly enriched on the nontranscribed strand (NTS) of yeast genes, particularly in BER-deficient strains, due to higher damage formation on the NTS and transcription-coupled repair of the transcribed strand (TS). These findings reveal the influence of chromatin on repair and mutagenesis of base lesions on a genome-wide scale and suggest a novel mechanism for transcription-associated mutation asymmetry, which is frequently observed in human cancers.

DNA碱基损伤是导致基因组不稳定的重要因素，但这些损伤的形成和修复如何受到基因组环境的影响并有助于诱变尚不清楚。在这里，我们描述了用烷基化剂甲磺酸甲酯（MMS）处理的酵母中单核苷酸分辨率下DNA碱基损伤，修复和诱变的全基因组图。对这些图谱的分析表明，染色质显着调节了烷基化损伤的碱基切除修复（BER），在核小体耗尽的区域修复速度更快，而在定位牢固的核小体中修复速度较慢，突变密度较高。核小体内病变的平移和旋转设置均会显着影响BER效率。而且，这种作用相对于核小体二联体轴是不对称的，并受组蛋白修饰的调节。我们的数据还表明，MMS诱导的腺嘌呤核苷酸突变在酵母基因的非转录链（NTS）上显着富集，特别是在BER缺失菌株中，这是由于NTS上形成的损伤更高以及转录链的转录偶联修复（TS）。这些发现揭示了染色质对全基因组范围内基础病变的修复和诱变的影响，并提出了一种转录相关突变不对称的新机制，这种机制在人类癌症中经常被观察到。由于在NTS上形成更高的损伤以及转录链（TS）的转录偶联修复。这些发现揭示了染色质对全基因组范围内基础病变的修复和诱变的影响，并提出了一种转录相关突变不对称的新机制，这种机制在人类癌症中经常被观察到。由于在NTS上形成更高的损伤以及转录链（TS）的转录偶联修复。这些发现揭示了染色质对全基因组范围内基础病变的修复和诱变的影响，并提出了一种转录相关突变不对称的新机制，这种机制在人类癌症中经常被观察到。