Abstract: 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 hNEIL2 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 beta-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 beta-elimination but demonstrated a lower affinity for DNA. Steady-state kinetics indicates that the P304T variant has its catalytic efficiency (in terms of k(cat)/K-M) 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.

Cite: Kakhkharova Z.I. , Zharkov D.O. , Grin I.R.
A Low-Activity Polymorphic Variant of Human NEIL2 DNA Glycosylase
International Journal of Molecular Sciences. 2022. V.23. N4. 2212 . DOI: 10.3390/ijms23042212 WOS Scopus OpenAlex

Dates:

Published print:

Feb 14, 2022

Identifiers:

Web of science:	WOS:000763151300001
Scopus:	2-s2.0-85124625797
OpenAlex:	W4212934250

Citing:

DB	Citing
Web of science	7
Scopus	7
OpenAlex	10

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