Genome-wide maps of alkylation damage, repair, and mutagenesis in yeast reveal mechanisms of mutational heterogeneity.
Genome-wide maps of alkylation damage, repair, and mutagenesis in yeast reveal mechanisms of mutational heterogeneity.
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DOI：
10.1101/gr.225771.117
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发表时间：
2017-10
期刊：
影响因子：
7
通讯作者：
Wyrick JJ
中科院分区：
文献类型：
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作者：
Mao P;Brown AJ;Malc EP;Mieczkowski PA;Smerdon MJ;Roberts SA;Wyrick JJ
DNA碱基损伤是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景观的影响并导致突变尚不清楚。在这里，我们描述了DNA碱基损伤、修复和突变的全基因组图谱，在单核苷酸分辨率下，酵母用烷基化剂甲基磺酸（MMS）处理。对这些图谱的分析表明，烷基化损伤的碱基切除修复（BER）受到染色质的显著调节，核小体缺失区域的修复速度更快，而核小体强定位区域的修复速度更慢，突变密度更高。核小体内病变的平移和旋转设置都显著影响BER效率；此外，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）上显著富集，特别是在ber缺陷菌株中，这是由于NTS上的更高损伤形成和转录偶联修复（TS）。这些发现揭示了染色质在全基因组范围内对碱基病变修复和突变的影响，并提出了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观察到。
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.
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影响因子：
3.3
作者：
Mao P;Wyrick JJ;Roberts SA;Smerdon MJ
通讯作者：
Smerdon MJ
影响因子：
14.9
作者：
Plosky BS;Frank EG;Berry DA;Vennall GP;McDonald JP;Woodgate R
通讯作者：
Woodgate R
影响因子：
64.8
作者：
Brogaard, Kristin;Xi, Liqun;Wang, Ji-Ping;Widom, Jonathan
通讯作者：
Widom, Jonathan
影响因子：
14.8
作者：
Ding J;Taylor MS;Jackson AP;Reijns MA
通讯作者：
Reijns MA
DOI：
10.1038/nrc3185
发表时间：
2012-01-12
期刊：
Nature reviews. Cancer
影响因子：
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作者：
通讯作者：
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