iMUT-seq: high-resolution DSB-induced mutation profiling reveals prevalent homologous-recombination dependent mutagenesis.
iMUT-seq: high-resolution DSB-induced mutation profiling reveals prevalent homologous-recombination dependent mutagenesis.
复制标题
DOI：
10.1038/s41467-023-44167-1
复制
发表时间：
2023-12-18
影响因子：
16.6
通讯作者：
Bushell, Martin
中科院分区：
文献类型：
--
作者：
Bader, Aldo S.;Bushell, Martin
DNA 双链断裂 (DSB) 是最具致突变性的 DNA 损伤形式，在癌症生物学、神经退行性疾病和衰老中发挥着重要作用。然而，研究 DSB 诱导的突变受到我们目前方法的限制。在这里，我们描述了 iMUT-seq，这是一种以高灵敏度和单核苷酸分辨率分析内源 DSB 周围 DSB 诱导的突变的技术。通过耗尽或抑制 20 个 DSB 修复因子，我们详细定义了它们的突变特征，揭示了 DSB 诱导突变机制的见解。值得注意的是，我们发现同源重组 (HR) 比之前想象的更具诱变性，由于 DNA 聚合酶错误，会在距离断裂较远的地方诱导普遍的碱基替换和单核苷酸缺失。同时，HR 减少易位，表明 HR 的主要作用具体是防止基因组重排。这里提出的结果提供了对 DSB 诱导突变的基本见解，并对我们对癌症生物学的理解和 DDR 靶向化疗药物的开发具有重要意义。 DNA 双链断裂 (DSB) 具有高度诱变性，使其成为许多病理学的核心。在这里，作者开发了一种高度灵敏的测序方法来研究 DSB 诱变，深入了解诱变结果并描述其潜在机制。
DNA double-strand breaks (DSBs) are the most mutagenic form of DNA damage, and play a significant role in cancer biology, neurodegeneration and aging. However, studying DSB-induced mutagenesis is limited by our current approaches. Here, we describe iMUT-seq, a technique that profiles DSB-induced mutations at high-sensitivity and single-nucleotide resolution around endogenous DSBs. By depleting or inhibiting 20 DSB-repair factors we define their mutational signatures in detail, revealing insights into the mechanisms of DSB-induced mutagenesis. Notably, we find that homologous-recombination (HR) is more mutagenic than previously thought, inducing prevalent base substitutions and mononucleotide deletions at distance from the break due to DNA-polymerase errors. Simultaneously, HR reduces translocations, suggesting a primary role of HR is specifically the prevention of genomic rearrangements. The results presented here offer fundamental insights into DSB-induced mutagenesis and have significant implications for our understanding of cancer biology and the development of DDR-targeting chemotherapeutics. DNA double-strand breaks (DSBs) are highly mutagenic making them central to many pathologies. Here, the authors developed a highly sensitive sequencing approach to study DSB mutagenesis, yielding insights into mutagenic outcomes and characterising their underlying mechanisms.
登录
查看更多内容
宇宙（癌症中的体细胞突变目录）数据库和网站。
影响因子：
8.8
作者：
Bamford, S;Dawson, E;Forbes, S;Clements, J;Pettett, R;Dogan, A;Flanagan, A;Teague, J;Futreal, PA;Stratton, MR;Wooster, R
通讯作者：
Wooster, R
影响因子：
14.9
作者：
Ahrabi S;Sarkar S;Pfister SX;Pirovano G;Higgins GS;Porter AC;Humphrey TC
通讯作者：
Humphrey TC
影响因子：
16.6
作者：
Cohen S;Puget N;Lin YL;Clouaire T;Aguirrebengoa M;Rocher V;Pasero P;Canitrot Y;Legube G
通讯作者：
Legube G
酿酒酵母中双链断裂和未加帽端粒处形成的受损单链 DNA 的超突变性。
影响因子：
4.5
作者：
Yang Y;Sterling J;Storici F;Resnick MA;Gordenin DA
通讯作者：
Gordenin DA
影响因子：
16
作者：
Ciccia A;Elledge SJ
通讯作者：
Elledge SJ