The dual role of DNA repair protein MGMT in cancer prevention and treatment

Peiying Bai; Tengjiao Fan; Guohui Sun; Xin Wang; Lijiao Zhao; Rugang Zhong

doi:10.1016/j.dnarep.2023.103449

The dual role of DNA repair protein MGMT in cancer prevention and treatment

DNA Repair (Amst). 2023 Mar:123:103449. doi: 10.1016/j.dnarep.2023.103449. Epub 2023 Jan 14.

Authors

Peiying Bai¹, Tengjiao Fan², Guohui Sun³, Xin Wang⁴, Lijiao Zhao¹, Rugang Zhong¹

Affiliations

¹ Beijing Key Laboratory of Environmental and Viral Oncology, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China.
² Beijing Key Laboratory of Environmental and Viral Oncology, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China; Department of Medical Technology, Beijing Pharmaceutical University of Staff and Workers, Beijing 100079, China.
³ Beijing Key Laboratory of Environmental and Viral Oncology, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China. Electronic address: sunguohui@bjut.edu.cn.
⁴ Department of Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100029, China.

PMID: 36680944
DOI: 10.1016/j.dnarep.2023.103449

Abstract

Alkylating agents are genotoxic chemicals that can induce and treat various types of cancer. This occurs through covalent bonding with cellular macromolecules, in particular DNA, leading to the loss of functional integrity under the persistence of modifications upon replication. O⁶-alkylguanine (O⁶-AlkylG) adducts are proposed to be the most potent DNA lesions induced by alkylating agents. If not repaired correctly, these adducts can result, at the molecular level, in DNA point mutations, chromosome aberrations, recombination, crosslinking, and single- and double-strand breaks (SSB/DSBs). At the cellular level, these lesions can result in malignant transformation, senescence, or cell death. O⁶-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein capable of removing the alkyl groups from O⁶-AlkylG adducts in a damage reversal process that can prevent the adverse biological effects of DNA damage caused by guanine O⁶-alkylation. MGMT can thereby defend normal cells against tumor initiation, however it can also protect tumor cells against the beneficial effects of chemotherapy. Hence, MGMT can play an important role in both the prevention and treatment of cancer; thus, it can be considered as a double-edged sword. From a clinical perspective, MGMT is a therapeutic target, and it is important to explore the rational development of its clinical exploitation.

Keywords: Alkylating agents; Cancer prevention; Dual role; MGMT; Tumor resistance.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Alkylating Agents
DNA / metabolism
DNA Damage
DNA Modification Methylases / metabolism
DNA Repair
DNA Repair Enzymes / metabolism
Humans
Neoplasms* / drug therapy
Neoplasms* / genetics
Neoplasms* / prevention & control
O(6)-Methylguanine-DNA Methyltransferase* / genetics
O(6)-Methylguanine-DNA Methyltransferase* / metabolism
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism

Substances

Alkylating Agents
DNA
DNA Modification Methylases
DNA Repair Enzymes
MGMT protein, human
O(6)-Methylguanine-DNA Methyltransferase
Tumor Suppressor Proteins