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Gutierrez et al. Cancer Drug Resist 2021;4:414-23 Cancer
DOI: 10.20517/cdr.2020.113 Drug Resistance

Review Open Access

DNA direct reversal repair and alkylating agent drug
resistance

Roberto Gutierrez , Timothy R. O’Connor 3
1,2
1 Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
2 Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA.
3 Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.

Correspondence to: Prof. Timothy R. O’Connor, Department of Cancer Biology, Beckman Research Institute, City of Hope,
Duarte, CA 91010, USA. E-mail: toconnor@coh.org
How to cite this article: Gutierrez R, O’Connor TR. DNA direct reversal repair and alkylating agent drug resistance. Cancer Drug
Resist 2021;4:414-23. http://dx.doi.org/10.20517/cdr.2020.113
Received: 9 Dec 2020 First Decision: 11 Jan 2021 Revised: 13 Jan 2021 Accepted: 22 Jan 2021 Available online: 19 Jun 2021

Academic Editors: Robert C.A.M. van Waardenburg, Godefridus J. Peters Copy Editor: Xi-Jun Chen Production Editor: Xi-Jun Chen

Abstract
DNA direct reversal repair (DRR) is unique in that no DNA synthesis is required to correct the error and therefore
repair via such mechanisms are error-free. In humans, DRR is carried out by two different pathways: the O6-
methylguanine-DNA methyltransferase (MGMT) and the alkylated DNA repair protein B (AlkB) homologs. The
use of alkylating agents is the standard of care for many cancers. However, the use of those drugs is usually halted
when resistance develops. This review will examine repair of alkylating agent damage mediated by DRR, resistance
mechanisms and potential ways to overcome such resistance.

Keywords: Direct reversal repair, O6-methylguanine-DNA methyltransferase, AlkB homologs, resistance to
alkylating agents

INTRODUCTION
DNA alkylating agents are still used for the treatment of many cancers. However, continued treatment with
alkylating agents, even in drug cocktails, generally results in drug resistance. Increasing the utility of those
drugs requires the understanding of the sources that oppose the therapeutic effects of alkylating agents.
One of the principal mechanisms that contributes to alkylating agent resistance is DNA repair.

DNA alkylation damage occurs at all bases. The level of DNA damage at the individual bases does not
correlate with the biological impact of the damage. Major damage sites at N7 of guanine does not generally

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0
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