RNA Editing of the Human DNA Glycosylase NEIL1 Alters Its Removal of 5-Hydroxyuracil Lesions in DNA.
RNA Editing of the Human DNA Glycosylase NEIL1 Alters Its Removal of 5-Hydroxyuracil Lesions in DNA.
复制标题
DOI：
10.1021/acs.biochem.1c00062
复制
发表时间：
2021-05-18
期刊：
影响因子：
2.9
通讯作者：
David, Sheila S.
中科院分区：
文献类型：
--
作者：
Yeo, Jongchan;Lotsof, Elizabeth R.;Anderson-Steele, Brittany M.;David, Sheila S.
编辑DNA修复糖基酶NEIL1的前mRNA导致在该酶的病变识别环中用Arg取代Lys。未编辑的(K242，UE)Neil去除DNA中胸腺嘧啶二醇损伤的速度比编辑的(R242，ED)NEIL1快~30倍。在这里，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突变的病变。NEIL1在单链DNA、泡状和凸起DNA背景下以及在与A配对的双链DNA碱基中催化低水平的5-OHU切除，发现在与G、T和C的碱基对中，UE比ED NEIL1去除5-OHU更快，并进行到更高的总体程度。此外，5-OHU附近错配的存在放大了ED亚型受阻的活性。然而，ED NEIL1对5-OHU：G和5-OHU：C双链的亲和力高于UE NEIL1。这些结果表明，Neil在检测和捕获不适当环境中的5-Ohu损伤方面发挥了重要作用，这种方式不会导致切除，以防止突变和链断裂。事实上，NEIL1从5-OHU中低效地去除5-OHU：复制过程中形成的BPS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，在炎症等细胞条件下，5-OHU修复会减少，从而增加NEIL1 RNA的编辑。打破两种Neil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。
Editing of the pre-mRNA of the DNA repair glycosylase NEIL1 results in substitution of Lys with Arg in the lesion recognition loop of the enzyme. Unedited (K242, UE) NEIL removes thymine glycol lesions in DNA ~30 times faster than edited (R242, Ed) 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. NEIL1 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 over 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 NEIL 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 bps formed during replication would thwart mutagenesis. Notably, non-productive engagement of 5-OHU by Ed NEIL1 suggests 5-OHU repair will be reduced under cellular conditions, such as inflammation, that increase NEIL1 RNA editing. Tipping the balance between the two NEIL isoforms may be a significant factor leading to genome instability.
登录
查看更多内容
影响因子：
4.8
作者：
Hegde, Pavana M.;Dutta, Arijit;Hegde, Muralidhar L.
通讯作者：
Hegde, Muralidhar L.
影响因子：
2.9
作者：
Jia, Lei;Shafirovich, Vladimir;Broyde, Suse
通讯作者：
Broyde, Suse
影响因子：
4.8
作者：
Dou, H;Mitra, S;Hazra, TK
通讯作者：
Hazra, TK
修复人类基因组中氧化损伤的新范例：确保在复制和辅助蛋白参与期间修复诱变碱病变的机制。
影响因子：
8
作者：
Dutta, Arijit;Yang, Chunying;Sengupta, Shiladitya;Mitra, Sankar;Hegde, Muralidhar L.
通讯作者：
Hegde, Muralidhar L.
影响因子：
7.4
作者：
Cadet J;Davies KJA;Medeiros MH;Di Mascio P;Wagner JR
通讯作者：
Wagner JR