Standard

A Low-Activity Polymorphic Variant of Human NEIL2 DNA Glycosylase. / Kakhkharova, Zarina I.; Zharkov, Dmitry O.; Grin, Inga R.

In: International Journal of Molecular Sciences, Vol. 23, No. 4, 2212, 01.02.2022.

Research output: Contribution to journalArticlepeer-review

Harvard

Kakhkharova, ZI, Zharkov, DO & Grin, IR 2022, 'A Low-Activity Polymorphic Variant of Human NEIL2 DNA Glycosylase', International Journal of Molecular Sciences, vol. 23, no. 4, 2212. https://doi.org/10.3390/ijms23042212

APA

Kakhkharova, Z. I., Zharkov, D. O., & Grin, I. R. (2022). A Low-Activity Polymorphic Variant of Human NEIL2 DNA Glycosylase. International Journal of Molecular Sciences, 23(4), [2212]. https://doi.org/10.3390/ijms23042212

Vancouver

Kakhkharova ZI, Zharkov DO, Grin IR. A Low-Activity Polymorphic Variant of Human NEIL2 DNA Glycosylase. International Journal of Molecular Sciences. 2022 Feb 1;23(4):2212. doi: 10.3390/ijms23042212

Author

Kakhkharova, Zarina I. ; Zharkov, Dmitry O. ; Grin, Inga R. / A Low-Activity Polymorphic Variant of Human NEIL2 DNA Glycosylase. In: International Journal of Molecular Sciences. 2022 ; Vol. 23, No. 4.

BibTeX

@article{d76cddb21e584e6b8faebb31cafcfc81,
title = "A Low-Activity Polymorphic Variant of Human NEIL2 DNA Glycosylase",
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 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 kcat /KM ) 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.",
keywords = "DNA damage, DNA glycosylases, DNA repair, NEIL2, Single-nucleotide polymorphisms, Variants of unknown significance",
author = "Kakhkharova, {Zarina I.} and Zharkov, {Dmitry O.} and Grin, {Inga R.}",
note = "Funding Information: Funding: This research was funded by Russian Science Foundation, grant number 17-14-01190P to I.R.G. Partial salary support from the Russian Ministry of Science and Higher Education (State funded budget project 121031300056-8 to D.O.Z.) is acknowledged. Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2022",
month = feb,
day = "1",
doi = "10.3390/ijms23042212",
language = "English",
volume = "23",
journal = "International Journal of Molecular Sciences",
issn = "1661-6596",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "4",

}

RIS

TY - JOUR

T1 - A Low-Activity Polymorphic Variant of Human NEIL2 DNA Glycosylase

AU - Kakhkharova, Zarina I.

AU - Zharkov, Dmitry O.

AU - Grin, Inga R.

N1 - Funding Information: Funding: This research was funded by Russian Science Foundation, grant number 17-14-01190P to I.R.G. Partial salary support from the Russian Ministry of Science and Higher Education (State funded budget project 121031300056-8 to D.O.Z.) is acknowledged. Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2022/2/1

Y1 - 2022/2/1

N2 - 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 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 kcat /KM ) 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.

AB - 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 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 kcat /KM ) 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.

KW - DNA damage

KW - DNA glycosylases

KW - DNA repair

KW - NEIL2

KW - Single-nucleotide polymorphisms

KW - Variants of unknown significance

UR - http://www.scopus.com/inward/record.url?scp=85124625797&partnerID=8YFLogxK

U2 - 10.3390/ijms23042212

DO - 10.3390/ijms23042212

M3 - Article

C2 - 35216329

AN - SCOPUS:85124625797

VL - 23

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 4

M1 - 2212

ER -

ID: 35535016