The Human DNA glycosylases NEIL1 and NEIL3 Excise Psoralen-Induced DNA-DNA Cross-Links in a Four-Stranded DNA Structure
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Date
2017
Authors
Martin, Peter R.
Couvé, Sophie
Zutterling, Caroline
Albelazi, Mustafa S.
Groisman, Regina
Matkarimov, Bakhyt T.
Parsons, Jason L.
Elder, Rhoderick H.
Saparbaev, Murat K.
Journal Title
Journal ISSN
Volume Title
Publisher
Nature Research
Abstract
Interstrand cross-links (ICLs) are highly cytotoxic DNA lesions that block DNA replication and transcription by preventing strand separation. Previously, we demonstrated that the bacterial and human DNA glycosylases Nei and NEIL1 excise unhooked psoralen-derived ICLs in three-stranded DNA via hydrolysis of the glycosidic bond between the crosslinked base and deoxyribose sugar. Furthermore, NEIL3 from Xenopus laevis has been shown to cleave psoralen- and abasic site-induced ICLs in Xenopus egg extracts. Here we report that human NEIL3 cleaves psoralen-induced DNA-DNA cross-links in three-stranded and four-stranded DNA substrates to generate unhooked DNA fragments containing either an abasic site or a psoralen-thymine monoadduct. Furthermore, while Nei and NEIL1 also cleave a psoralen-induced four-stranded DNA substrate to generate two unhooked DNA duplexes with a nick, NEIL3 targets both DNA strands in the ICL without generating single-strand breaks. The DNA substrate specificities of these Nei-like enzymes imply the occurrence of long uninterrupted three- and four-stranded crosslinked DNA-DNA structures that may originate in vivo from DNA replication fork bypass of an ICL. In conclusion, the Nei-like DNA glycosylases unhook psoralen-derived ICLs in various DNA structures via a genuine repair mechanism in which complex DNA lesions can be removed without generation of highly toxic double-strand breaks.
Description
Keywords
DNA, Research Subject Categories::TECHNOLOGY, Interstrand cross-links, ICLs, NEIL1, Furanocoumarins
Citation
Martin, P. R., Couvé, S., Zutterling, C., Albelazi, M. S., Groisman, R., Matkarimov, B. T., Parsons, J. L., Elder, R. H., & Saparbaev, M. K. (2017). The Human DNA glycosylases NEIL1 and NEIL3 Excise Psoralen-Induced DNA-DNA Cross-Links in a Four-Stranded DNA Structure. Scientific Reports, 7(1). https://doi.org/10.1038/s41598-017-17693-4