Enzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development.
Enzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development.
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从DNA中酶促去除核糖核苷酸对于哺乳动物的基因组完整性和发育至关重要。
DOI：
10.1016/j.cell.2012.04.011
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发表时间：
2012-05-25
期刊：
影响因子：
64.5
通讯作者：
Jackson AP
中科院分区：
文献类型：
--
作者：
Reijns MA;Rabe B;Rigby RE;Mill P;Astell KR;Lettice LA;Boyle S;Leitch A;Keighren M;Kilanowski F;Devenney PS;Sexton D;Grimes G;Holt IJ;Hill RE;Taylor MS;Lawson KA;Dorin JR;Jackson AP
基因组DNA中存在核糖核苷酸是不可取的，因为它们对水解的敏感性增加。识别和处理这种嵌入的核苷酸的核糖核酸酶(RNase)H酶存在于生命的所有领域。然而，在单细胞生物体中，如发芽酵母，它们并不是细胞存活甚至有效增殖所必需的，而在人类中，RNaseH2亚型突变会导致神经炎性疾病艾卡迪-古蒂埃综合征。在这里，我们报告了RNaseH2是小鼠体内的一种必不可少的酶，从原肠发育到胚胎生长都需要它。RNaseH2缺失的胚胎在其基因组DNA(每细胞1,000,000,000)中积累了大量单(或双)核苷酸，导致基因组不稳定和依赖于P53的DNA损伤反应。我们的发现确立了RNaseH2是去除核苷酸所需的关键哺乳动物基因组监控酶，并证明了核苷酸是复制细胞中最常见的内源性核苷酸碱基损伤。►核糖核酸酶是小鼠基因组中最常见的核苷酸碱基损伤，►核糖核酸酶H2是去除核苷酸所需的关键基因组监视酶，►核糖核酸酶H2是哺乳动物发育所必需的，没有核糖核酸酶H2的细胞表现出基因组的不稳定性和P53途径的激活►聚合酶可以在每个细胞中复制一百万个以上的核苷酸，使核苷酸成为最丰富的一种DNA损伤。RNaseH2消除了这种“损伤”，在基因组监测中起着至关重要的作用，是胚胎发育所必需的。
The presence of ribonucleotides in genomic DNA is undesirable given their increased susceptibility to hydrolysis. Ribonuclease (RNase) H enzymes that recognize and process such embedded ribonucleotides are present in all domains of life. However, in unicellular organisms such as budding yeast, they are not required for viability or even efficient cellular proliferation, while in humans, RNase H2 hypomorphic mutations cause the neuroinflammatory disorder Aicardi-Goutières syndrome. Here, we report that RNase H2 is an essential enzyme in mice, required for embryonic growth from gastrulation onward. RNase H2 null embryos accumulate large numbers of single (or di-) ribonucleotides embedded in their genomic DNA (>1,000,000 per cell), resulting in genome instability and a p53-dependent DNA-damage response. Our findings establish RNase H2 as a key mammalian genome surveillance enzyme required for ribonucleotide removal and demonstrate that ribonucleotides are the most commonly occurring endogenous nucleotide base lesion in replicating cells. ► Ribonucleotides are the most common nucleotide base lesion in the mouse genome ► RNase H2 is a key genome surveillance enzyme required for removal of nucleotides ► RNase H2 is essential for mammalian development ► Without RNase H2, cells exhibit genome instability and p53 pathway activation DNA polymerases can incorporate more than a million ribonucleotides into replicating mouse DNA in each cell, making ribonucleotides the most abundant kind of DNA lesion. RNase H2, which removes this “damage,” has an essential role in genome surveillance and is required for embryonic development.
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DOI：
10.1093/bfgp/elm022
发表时间：
2007-09-01
期刊：
Briefings in Functional Genomics & Proteomics
影响因子：
--
作者：
Friedel, Roland H.;Seisenberger, Claudia;Wurst, Wolfgang
通讯作者：
Wurst, Wolfgang
影响因子：
14.9
作者：
Bubeck D;Reijns MA;Graham SC;Astell KR;Jones EY;Jackson AP
通讯作者：
Jackson AP
影响因子：
16
作者：
Ciccia A;Elledge SJ
通讯作者：
Elledge SJ
影响因子：
9.2
作者：
Esposito, G;Godin, I;Rajewsky, K
通讯作者：
Rajewsky, K
影响因子：
16
作者：
Cerritelli, SM;Frolova, EG;Crouch, RJ
通讯作者：
Crouch, RJ