Expression of a germline variant in the N-terminal domain of the human DNA glycosylase NTHL1 induces cellular transformation without impairing enzymatic function or substrate specificity

Published

June 16, 2020

Author(s)

Carolyn G. Marsden, Pawel Jaruga, Erdem Coskun, Robyn L. Maher, David S. Pederson, Miral M. Dizdar, Joann B. Sweasy

Abstract

Oxidatively-induced DNA damage, widely accepted as a key player in the onset of cancer, is predominantly repaired by base excision repair (BER). BER is initiated by DNA glycosylases, which locate and remove damaged bases from DNA. NTHL1 is a bifunctional DNA glycosylase in mammalian cells that predominantly removes oxidized pyrimidines. In this study, we investigated a germline variant in the N-terminal domain of NTHL1, R33K. Expression of NTHL1 R33K in human MCF10A cells resulted in increased proliferation and anchorage-independent growth compared to NTHL1 WT-expressing cells. However, wt-NTHL1 and R33K-NTHL1 exhibited similar substrate specificity, excision kinetics, and enzyme turnover in vitro and in vivo. The results of this study indicate an important function of R33 in BER that is disrupted by the R33K mutation. Furthermore, the cellular transformation induced by R33K-NTHL1 expression suggests that humans harboring this germline variant may be at increased risk for cancer incidence.

Citation

Oncotarget

Volume

11

Issue

24

Pub Type

Journals

Download Paper

DOI Link

Keywords

human DNA glycosylase NTHL1, germline variant, oxidative DNA damage, BER, NTHL1 R33K

Citation

Marsden, C. , Jaruga, P. , Coskun, E. , Maher, R. , Pederson, D. , Dizdar, M. and Sweasy, J. (2020), Expression of a germline variant in the N-terminal domain of the human DNA glycosylase NTHL1 induces cellular transformation without impairing enzymatic function or substrate specificity, Oncotarget, [online], https://doi.org/10.18632/oncotarget.27548 (Accessed October 20, 2025)