RNases H1 and H2: guardians of the stability of the nuclear genome when supply of dNTPs is limiting for DNA synthesis.
RNases H1 and H2: guardians of the stability of the nuclear genome when supply of dNTPs is limiting for DNA synthesis.
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DOI：
10.1007/s00294-020-01086-8
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发表时间：
2020-12
期刊：
影响因子：
2.5
通讯作者：
El Hage A
中科院分区：
文献类型：
--
作者：
Cerritelli SM;El Hage A
RNA/DNA杂合体由RNase H1和H2处理，而嵌入基因组DNA中的单个核糖核苷单磷酸（rNMP）通过无错误的、RNase H2依赖的核糖核苷酸切除修复（RER）途径去除。然而，在不存在RER的情况下，拓扑异构酶1（Top1）可以以诱变方式切割单个基因组rNMP。在RNase H2缺陷型小鼠中，基因组rNMP的积累超过耐受阈值会导致灾难性的基因组不稳定性，从而导致胚胎死亡。在人类中，RNase H2的缺乏会诱发自身免疫性疾病Aicardi-Goutières综合征和系统性红斑狼疮，并导致皮肤癌和肠癌。最近，我们报道，在酿酒酵母中，核糖核苷酸还原酶（RNR）的主要催化亚基Rnr 1的耗尽，它将核糖核苷酸转化为脱氧核糖核苷酸，导致细胞死亡的情况下，RNA酶H1和H2。我们假设，在复制应激和受损的DNA修复引起的供应不足的脱氧核糖核苷三磷酸（dNTPs），细胞不能生存的积累持久的RNA/DNA杂交。值得注意的是，我们发现缺乏RNase H2的细胞在不存在Rnr 1的情况下积累的基因组rNMP是存在Rnr 1的情况下的2.5倍。当基因组rNMP的负荷在复制型DNA聚合酶变体的存在下进一步增加时，该复制型DNA聚合酶变体在前导链或滞后链中过度掺入rNMP，缺失Rnr 1和RNA酶H2的细胞遭受严重的生长缺陷。这些在没有Top1的情况下是颠倒的。因此，在缺乏RNase H2和含有有限供应的dNTPs的细胞中，存在与Top1介导的DNA损伤紧密相关的基因组核糖核苷酸积累的耐受阈值。在这篇小型综述中，我们描述了核糖核酸酶H2或核糖核酸酶H1和H2的损失对核基因组完整性和芽殖酵母细胞活力的影响，这些芽殖酵母细胞受到极低dNTPs供应的挑战。我们进一步提出，我们在芽殖酵母中的发现可以为研究哺乳动物RNR在RNase H2相关疾病中的潜在作用铺平道路。
RNA/DNA hybrids are processed by RNases H1 and H2, while single ribonucleoside-monophosphates (rNMPs) embedded in genomic DNA are removed by the error-free, RNase H2-dependent ribonucleotide excision repair (RER) pathway. In the absence of RER, however, topoisomerase 1 (Top1) can cleave single genomic rNMPs in a mutagenic manner. In RNase H2-deficient mice, the accumulation of genomic rNMPs above a threshold of tolerance leads to catastrophic genomic instability that causes embryonic lethality. In humans, deficiencies in RNase H2 induce the autoimmune disorders Aicardi–Goutières syndrome and systemic lupus erythematosus, and cause skin and intestinal cancers. Recently, we reported that in Saccharomyces cerevisiae, the depletion of Rnr1, the major catalytic subunit of ribonucleotide reductase (RNR), which converts ribonucleotides to deoxyribonucleotides, leads to cell lethality in absence of RNases H1 and H2. We hypothesized that under replicative stress and compromised DNA repair that are elicited by an insufficient supply of deoxyribonucleoside-triphosphates (dNTPs), cells cannot survive the accumulation of persistent RNA/DNA hybrids. Remarkably, we found that cells lacking RNase H2 accumulate ∼ 5-fold more genomic rNMPs in absence than in presence of Rnr1. When the load of genomic rNMPs is further increased in the presence of a replicative DNA polymerase variant that over-incorporates rNMPs in leading or lagging strand, cells missing both Rnr1 and RNase H2 suffer from severe growth defects. These are reversed in absence of Top1. Thus, in cells lacking RNase H2 and containing a limiting supply of dNTPs, there is a threshold of tolerance for the accumulation of genomic ribonucleotides that is tightly associated with Top1-mediated DNA damage. In this mini-review, we describe the implications of the loss of RNase H2, or RNases H1 and H2, on the integrity of the nuclear genome and viability of budding yeast cells that are challenged with a critically low supply of dNTPs. We further propose that our findings in budding yeast could pave the way for the study of the potential role of mammalian RNR in RNase H2-related diseases.
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影响因子：
13.8
作者：
Cerritelli SM;Crouch RJ
通讯作者：
Crouch RJ
影响因子：
16.6
作者：
Ahuja AK;Jodkowska K;Teloni F;Bizard AH;Zellweger R;Herrador R;Ortega S;Hickson ID;Altmeyer M;Mendez J;Lopes M
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影响因子：
14.9
作者：
Chon H;Sparks JL;Rychlik M;Nowotny M;Burgers PM;Crouch RJ;Cerritelli SM
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在Aicardi-Goutières综合征中突变的RNase H2促进了LINE-1逆转录位。
DOI：
10.15252/embj.201798506
发表时间：
2018-08-01
期刊：
The EMBO journal
影响因子：
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作者：
Benitez-Guijarro M;Lopez-Ruiz C;Tarnauskaitė Ž;Murina O;Mian Mohammad M;Williams TC;Fluteau A;Sanchez L;Vilar-Astasio R;Garcia-Canadas M;Cano D;Kempen MH;Sanchez-Pozo A;Heras SR;Jackson AP;Reijns MA;Garcia-Perez JL
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影响因子：
16.6
作者：
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通讯作者：
Kunkel TA