A Low-Activity Polymorphic Variant of Human NEIL2 DNA Glycosylase

Human NEIL2 DNA glycosylase (hNEIL2) is a base excision repair protein that removes oxidative lesions from DNA. A distinctive feature of hNEIL2 is its preference for the lesions in bubbles and other non-canonical DNA structures. Although a number of associations of polymorphisms in the gene were rep...

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Bibliographic Details
Published in:	International journal of molecular sciences Vol. 23; no. 4; p. 2212
Main Authors:	Kakhkharova, Zarina I, Zharkov, Dmitry O, Grin, Inga R
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 17-02-2022 MDPI
Subjects:	Agreements Algorithms Amino Acid Sequence Base excision repair Breast cancer Colorectal cancer Deoxyribonucleic acid DNA DNA - genetics DNA Breaks, Single-Stranded DNA damage DNA Damage - genetics DNA glycosylase DNA glycosylases DNA Glycosylases - genetics DNA repair DNA Repair - genetics DNA-(Apurinic or Apyrimidinic Site) Lyase - genetics Enzymes Epidemiology Gene expression Humans Lesions Mutation NEIL2 Polymorphism, Genetic - genetics Proteins Repair Roles single-nucleotide polymorphisms Single-stranded DNA Tumors variants of unknown significance DNA glycosylases NEIL2 variants of unknown significance DNA repair single-nucleotide polymorphisms DNA damage
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Summary:	Human NEIL2 DNA glycosylase (hNEIL2) is a base excision repair protein that removes oxidative lesions from DNA. A distinctive feature of hNEIL2 is its preference for the lesions in bubbles and other non-canonical DNA structures. Although a number of associations of polymorphisms in the gene were reported, there is little data on the functionality of the encoded protein variants, as follows: only hNEIL2 R103Q was described as unaffected, and R257L, as less proficient in supporting the repair in a reconstituted system. Here, we report the biochemical characterization of two hNEIL2 variants found as polymorphisms in the general population, R103W and P304T. Arg103 is located in a long disordered segment within the N-terminal domain of hNEIL2, while Pro304 occupies a position in the β-turn of the DNA-binding zinc finger motif. Similar to the wild-type protein, both of the variants could catalyze base excision and nick DNA by β-elimination but demonstrated a lower affinity for DNA. Steady-state kinetics indicates that the P304T variant has its catalytic efficiency (in terms of / ) reduced ~5-fold compared with the wild-type hNEIL2, whereas the R103W enzyme is much less affected. The P304T variant was also less proficient than the wild-type, or R103W hNEIL2, in the removal of damaged bases from single-stranded and bubble-containing DNA. Overall, hNEIL2 P304T could be worthy of a detailed epidemiological analysis as a possible cancer risk modifier.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1422-0067 1661-6596 1422-0067
DOI:	10.3390/ijms23042212