Genome-wide Map of R-Loop-Induced Damage Reveals How a Subset of R-Loops Contributes to Genomic Instability.
Genome-wide Map of R-Loop-Induced Damage Reveals How a Subset of R-Loops Contributes to Genomic Instability.
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DOI：
10.1016/j.molcel.2018.06.037
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发表时间：
2018-08-16
期刊：
影响因子：
16
通讯作者：
Koshland D
中科院分区：
文献类型：
--
作者：
Costantino L;Koshland D
与R环相关的DNA-RNA杂合体促进DNA损伤和基因组不稳定性。不同基因组位点的杂交体引起DNA损伤的能力尚不清楚，从杂交体到损伤的机制也知之甚少。在这里，我们采用了一种新的策略来映射和表征芽殖酵母中全基因组杂交诱导损伤的位点。我们表明，杂交去除是必不可少的生命，因为持久的杂交导致不可挽回的DNA损伤和细胞死亡。我们确定，一个子集的杂交是容易造成损害，染色体的杂交背景显着影响他们的能力，以诱导损害。此外，持久性杂交影响修复途径，通过两种不同的机制产生大区域的ssDNA，可能是切除和再复制。这些受损的区域可能是总染色体重排的潜在前体，如与R环和癌症相关的缺失和重复。一句话总结：DNA-RNA杂交体的持续存在导致不同的异常DNA损伤结构的形成。RNA可以与基因组位点杂交，产生DNA-RNA杂交体和称为R环的ssDNA细丝，这可能导致DNA损伤。Constantino和Koshland发现，只有一部分持续性R环会造成不可修复的损害。当杂交体在受损区域持续存在时，它会阻止正确的修复，产生基因组不稳定的潜在前兆。
DNA-RNA hybrids associated with R-loops promote DNA damage and genomic instability. The capacity of hybrids at different genomic sites to cause DNA damage was not known, and the mechanisms leading from hybrid to damage were poorly understood. Here, we adopt a new strategy to map and characterize the sites of hybrid-induced damage genome-wide in budding yeast. We show that hybrid removal is essential for life because persistent hybrids cause irreparable DNA damage and cell death. We identify that a subset of hybrids is prone to cause damage, and that the chromosomal context of hybrids dramatically impacts their ability to induce damage. Furthermore, persistent hybrids affect the repair pathway generating large regions of ssDNA by two distinct mechanisms, likely resection and re-replication. These damaged regions may act as potential precursors to gross chromosomal rearrangements like deletions and duplications that are associated with R-loops and cancers. One Sentence Summary: Persistence of DNA-RNA hybrids leads to the formation of different aberrant DNA damage structures. RNA can hybridize to genomic loci creating DNA-RNA hybrids and ssDNA filaments called R-loops, which can cause DNA damage. Constantino and Koshland discovered that only a subset of persistent R-loops causes irreparable damage. When the hybrid persists in the damaged region, it blocks correct repair, generating potential precursors of genome instability.
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影响因子：
64.5
作者：
Li, XL;Manley, JL
通讯作者：
Manley, JL
影响因子：
1.2
作者：
Grubb, Jennifer;Brown, M. Scott;Bishop, Douglas K.
通讯作者：
Bishop, Douglas K.
转录复制冲突取向调节R环水平并激活不同的DNA损伤反应。
影响因子：
64.5
作者：
Hamperl S;Bocek MJ;Saldivar JC;Swigut T;Cimprich KA
通讯作者：
Cimprich KA
影响因子：
4.5
作者：
Becherel OJ;Yeo AJ;Stellati A;Heng EY;Luff J;Suraweera AM;Woods R;Fleming J;Carrie D;McKinney K;Xu X;Deng C;Lavin MF
通讯作者：
Lavin MF
影响因子：
5.3
作者：
French, Sarah L.;Sikes, Martha L.;Beyer, Ann L.
通讯作者：
Beyer, Ann L.