Regulation of DNA Alkylation Damage Repair: Lessons and Therapeutic Opportunities.
Alkylation chemotherapy is one of the most widely used systemic therapies for cancer. While somewhat effective, clinical responses and toxicities of these agents are highly variable. A major contributing factor for this variability is the numerous distinct lesions that are created upon alkylation damage. These adducts activate multiple repair pathways. There is mounting evidence that the individual pathways function cooperatively, suggesting that coordinated regulation of alkylation repair is critical to prevent toxicity. Furthermore, some alkylating agents produce adducts that overlap with newly discovered methylation marks, making it difficult to distinguish between bona fide damaged bases and so-called 'epigenetic' adducts. Here, we discuss new efforts aimed at deciphering the mechanisms that regulate these repair pathways, emphasizing their implications for cancer chemotherapy.
Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
Jennifer M
JM
Soll
Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA. Electronic address: rwsobol@health.southalabama.edu.
Robert W
RW
Sobol
Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St Louis, MO 63110, USA. Electronic address: Mosammaparast@wustl.edu.
Nima
N
Mosammaparast
D000478:Alkylation / Q000187:drug effects; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism
D018906:Antineoplastic Agents, Alkylating; D004273:DNA, Neoplasm
AlkB; MGMT; alkylation chemotherapy; base excision repair