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RNases H1 and H2: guardians of the stability of the nuclear genome when supply of dNTPs is limiting for DNA synthesis.
Current Genetics ( IF 2.5 ) Pub Date : 2020-09-04 , DOI: 10.1007/s00294-020-01086-8
Susana M Cerritelli 1 , Aziz El Hage 2
Affiliation  

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.



中文翻译:

RNases H1 和 H2:当 dNTP 的供应限制 DNA 合成时,核基因组稳定性的守护者。

RNA/DNA 杂交体由 RNases H1 和 H2 处理,而嵌入基因组 DNA 的单个核糖核苷单磷酸 (rNMP) 则通过无错误、依赖 RNase H2 的核糖核苷酸切除修复 (RER) 途径去除。然而,在没有 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,从而导致胚胎致死。在人类中,RNase H2 的缺乏会导致自身免疫性疾病 Aicardi-Goutières 综合征和系统性红斑狼疮,并导致皮肤癌和肠癌。最近,我们报道了在酿酒酵母中Rnr1 是核糖核苷酸还原酶 (RNR) 的主要催化亚基,可将核糖核苷酸转化为脱氧核糖核苷酸,Rnr1 的消耗导致细胞在缺乏 RNases H1 和 H2 的情况下致死。我们假设,在由脱氧核糖核苷三磷酸 (dNTP) 供应不足引起的复制压力和受损的 DNA 修复下,细胞无法在持久性 RNA/DNA 杂交体的积累中存活下来。值得注意的是,我们发现缺乏 RNase H2 的细胞在缺乏 Rnr1 的情况下积累了约 5 倍的基因组 rNMP。当基因组 rNMP 的负载在存在复制 DNA 聚合酶变体的情况下进一步增加时,该变体在前导链或滞后链中过度掺入 rNMP,同时缺失 Rnr1 和 RNase H2 的细胞会遭受严重的生长缺陷。在没有 Top1 的情况下,这些会被逆转。因此,在缺乏 RNase H2 且含有有限 dNTP 供应的细胞中,对于与 Top1 介导的 DNA 损伤密切相关的基因组核糖核苷酸的积累存在耐受阈值。在这篇小型综述中,我们描述了 RNase H2 或 RNases H1 和 H2 缺失对核基因组完整性和出芽酵母细胞活力的影响,这些细胞受到极低的 dNTP 供应挑战。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。或 RNases H1 和 H2,关于核基因组的完整性和出芽酵母细胞的活力,这些细胞受到极低的 dNTP 供应挑战。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。或 RNases H1 和 H2,关于核基因组的完整性和出芽酵母细胞的活力,这些细胞受到极低的 dNTP 供应挑战。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。

更新日期:2020-09-05
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