Bevin Engelward, Sc.D.; John Essigmannm, Ph.D.
Massachusetts Institute of Technology
P42ES027707, P30ES002109, T32ES007020
NIEHS-funded researchers discovered a DNA-repair molecule that affects susceptibility to disease in mice exposed to N-nitrosodimethylamine (NDMA). Alkyladenine DNA glycosylase (AAG) is known to be an important player in DNA repair, but this study revealed for the first time that too much or too little can control the switch between cancer and lethality.
NDMA is a DNA-damaging agent found in chemical waste and produced as a byproduct of certain wastewater treatment processes. The team previously developed a specialized mouse model to compare mice with deficient or overexpressed AAG for DNA and tissue damage, mutations, and cancer resulting from NDMA exposure. They also integrated a suite of molecular, cellular, and physiological analyses to explore the underlying mechanisms involved.
Mice deficient in AAG had more DNA mutations and cancer when exposed to NDMA than normal mice. Mice with high levels of AAG were protected from mutations and cancer following NDMA exposure but had more tissue damage and lower survival rates than normal mice. NDMA exposure also damaged DNA in normal mice, but they seemed to be somewhat protected from the extremes associated with too much or too little AAG.
According to the authors, AAG controls whether cells survive DNA damage and whether they will eventually develop mutations and cancer. They explained that these findings may help identify low- or high-risk populations since humans vary by as much as 20-fold in AAG activity levels, and may be useful to inform precision medicine to treat cancer.
Citation: Kay JE, Corrigan JJ, Armijo AL, Nazari IS, Kohale IN, Torous DK, Avlasevich SL, Croy RG, Wadduwage DN, Carrasco SE, Dertinger SD, White FM, Essigmann JM, Samson LD, Engelward BP. 2021. Excision of mutagenic replication-blocking lesions suppresses cancer but promotes cytotoxicity and lethality in nitrosamine-exposed mice. Cell Rep 34(11):108864.