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Compromised Genomic Maintenance Integrity after Non‐Lethal Doses of Cadmium
Author(s) -
Sherrer Shanen M.,
Lundh Linnea M.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.457.24
Subject(s) - cadmium , dna repair , dna damage , carcinogenesis , carcinogen , dna polymerase , cancer research , dna mismatch repair , polymerase , biology , dna , genetics , chemistry , microbiology and biotechnology , cancer , organic chemistry
The integrity of an organism's genome can be compromised and promote carcinogenesis without structural modifiers under certain conditions. One such condition occurs when cadmium is present since cadmium exposure is linked to lung cancer and other cancers with little molecular details known. In this study, we first observed that the productivity of replicative DNA polymerases is greatly reduced in the presence of cadmium. This cadmium‐induced decrease in DNA polymerase efficiency can lead to an increase in genetic mutations that become substrates for the DNA mismatch repair (MMR). Deficiency of MMR also increases spontaneous mutability and is the cause of some sporadic cancers and colon cancer. Interestingly, cadmium selectively inhibits 3′‐directed MMR, a reaction that absolutely depends on human MutLα (hMutLα), and that can only be restored with supplementation of endonuclease‐active hMutLα. We also found that cadmium specifically inactivates hMutLα endonuclease activity. Based on our findings, it is suggested that some of the biological effects of cadmium on MMR are the result of deminished replicative DNA polymerase activity, and selective inhibition of zinc‐dependent hMutLα. Thus, our work provides new molecular details on how cadmium acts as an environmental carcinogen and mutagen. Support or Funding Information This work was partially financially supported by St. Mary's College of Maryland. L. Lundh was supported by the Cove Point Natural Heritage Trust's Ruth Mathes Scholarship. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .