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首页> 外文期刊>Biochemistry >RNA Editing of the Human DNA Glycosylase NEIL1 Alters Its Removal of 5-Hydroxyuracil Lesions in DNA
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RNA Editing of the Human DNA Glycosylase NEIL1 Alters Its Removal of 5-Hydroxyuracil Lesions in DNA

机译：人DNA糖基酶Neil1的RNA编辑改变其在DNA中除去5-羟基尿嘧啶病变

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摘要

Editing of the pre-mRNA of the DNA repair glycosylase NEIL1 results in substitution of a Lys with Arg in the lesion recognition loop of the enzyme. Unedited (UE, Lys242) NEIL1 removes thymine glycol lesions in DNA similar to 30 times faster than edited (Ed, Arg242) NEIL1. Herein, we evaluated recognition and excision mediated by UE and Ed NEIL1 of 5-hydroxyuracil (5-OHU), a highly mutagenic lesion formed via oxidation of cytosine. Both NEIL1 isoforms catalyzed low levels of 5-OHU excision in single-stranded DNA, bubble and bulge DNA contexts and in duplex DNA base paired with A. Removal of 5-OHU in base pairs with G, T, and C was found to be faster and proceed to a higher overall extent with UE than with Ed NEIL1. In addition, the presence of mismatches adjacent to 5-OHU magnified the hampered activity of the Ed isoform. However, Ed NEIL1 was found to exhibit higher affinity for 5-OHU:G and 5-OHU:C duplexes than UE NEIL1. These results suggest that NEIL1 plays an important role in detecting and capturing 5-OHU lesions in inappropriate contexts, in a manner that does not lead to excision, to prevent mutations and strand breaks. Indeed, inefficient removal of 5-OHU by NEIL1 from 5-OHU:A base pairs formed during replication would thwart mutagenesis. Notably, nonproductive engagement of 5-OHU by Ed NEIL1 suggests the extent of 5-OHU repair will be reduced under cellular conditions, such as inflammation, that increase the extent of NEIL1 RNA editing. Tipping the balance between the two NEIL1 isoforms may be a significant factor leading to genome instability.
机译：编辑DNA修复糖基化酶NEIL1的前mRNA会导致该酶的损伤识别环中的Lys被Arg取代。未编辑（UE，Lys242）NEIL1去除DNA中的胸腺嘧啶乙二醇损伤的速度是编辑（Ed，Arg242）NEIL1的30倍。在此，我们评估了UE和Ed NEIL1介导的5-羟基尿嘧啶（5-OHU）的识别和切除，5-OHU是一种通过胞嘧啶氧化形成的高度致突变病变。两种NEIL1亚型均催化单链DNA、泡状和凸起DNA以及与A配对的双链DNA碱基中的低水平5-OHU切除。发现与Ed NEIL1相比，在G、T和C碱基对中去除5-OHU的速度更快，总体程度更高。此外，5-OHU附近存在的错配放大了Ed亚型的活性受阻。然而，Ed NEIL1被发现比UE NEIL1对5-OHU:G和5-OHU:C双工体表现出更高的亲和力。这些结果表明，NEIL1在检测和捕获不适当情况下的5-OHU病变方面起着重要作用，其方式不会导致切除，以防止突变和链断裂。事实上，NEIL1从5-OHU中低效去除5-OHU：复制过程中形成的碱基对会阻碍突变。值得注意的是，Ed NEIL1对5-OHU的非生产性参与表明，5-OHU修复的程度在细胞条件下会降低，例如炎症，这会增加NEIL1 RNA编辑的程度。打破两种NEIL1亚型之间的平衡可能是导致基因组不稳定的一个重要因素。

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