@article{989873a90fb248d7a6bf7296c0a0e783,
title = "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",
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.",
keywords = "Base excision repair, Cellular transformation, Germline variant, NTHL1",
author = "Marsden, {Carolyn G.} and Pawel Jaruga and Erdem Coskun and Maher, {Robyn L.} and Pederson, {David S.} and Miral Dizdaroglu and Sweasy, {Joann B.}",
note = "Funding Information: We would like to acknowledge members of the Sweasy and Pederson labs for their discussions and advice. Certain commercial equipment or materials are identified in this paper in order to specify adequately the experimental procedure. Such identification does not imply recommendation or endorsement by the National Institute of Standards and Technology, nor does it imply that the materials or equipment identified are necessarily the best available for the purpose. DNA samples isolated from human MCF10A cells at the University of Vermont were provided to the National Institute of Standards and Technology pursuant to a Material Transfer Agreement between the two institutions. This work was supported in part by P01CA98993 from the National Cancer Institute. Publisher Copyright: {\textcopyright} Marsden et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
year = "2020",
month = jun,
day = "16",
doi = "10.18632/oncotarget.27548",
language = "English (US)",
volume = "11",
pages = "2262--2272",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "24",
}