Defects in Base Excision Repair Sensitize Cells to Manganese inS. cerevisiae

Abstract

Manganese (Mn) is essential for normal physiologic functioning; therefore, deficiencies and excess intake of manganese can result in disease. In humans, prolonged exposure to manganese causes neurotoxicity characterized by Parkinson-like symptoms. Mn2+ has been shown to mediate DNA damage possibly through the generation of reactive oxygen species. In a recent publication, we showed that Mn induced oxidative DNA damage and caused lesions in thymines. This study further investigates the mechanisms by which cells process Mn2+-mediated DNA damage using the yeast S. cerevisiae. The strains most sensitive to Mn2+ were those defective in base excision repair, glutathione synthesis, and superoxide dismutase mutants. Mn2+ caused a dose-dependent increase in the accumulation of mutations using the CAN1 and lys2-10A mutator assays. The spectrum of CAN1 mutants indicates that exposure to Mn results in accumulation of base substitutions and frameshift mutations. The sensitivity of cells to Mn2+ as well as its mutagenic effect was reduced by N-acetylcysteine, glutathione, and Mg2+. These data suggest that Mn2+ causes oxidative DNA damage that requires base excision repair for processing and that Mn interferes with polymerase fidelity. The status of base excision repair may provide a biomarker for the sensitivity of individuals to manganese.

DNA Damage Induced by Manganese

“…The authors proposed further that the status of BER might provide a biomarker for the Mn sensitivity of individuals. 65 Overexpression of RAD23, a well-conserved protein involved in DNA repair (NER) and proteosomal degradation, in S. cerevisiae resulted in a reduction of Mn toxicity by lowering Mn levels. However, data suggest that the RAD23-induced reversal of manganese toxicity reflects its role in protein quality control, not DNA repair.…”

Effects of Manganese on Genomic Integrity in the Multicellular Model Organism Caenorhabditis elegans

“…While BER incision activity was measured in mice with varying trace element status [65], the effect of Mn alone on DNA repair efficiency has yet to be studied. Other studies focus on the sensitivity of different BER deficient species/cells towards Mn, but not the adverse consequences of Mn on DNA repair (e.g., [66]). Further research is therefore called for, especially considering the importance of BER in post-mitotic cells such as neurons [41].…”

EKOGENOTOKSISITAS LIMBAH CAIR BATIK DAN EFEK ANTIMUTAGENIK Lemna minor TERHADAP ERITROSIT IKAN NILA (Oreochromis niloticus)

“…Selain berperan langsung terhadap DNA, radikal bebas juga memicu kerusakan enzimenzim antioksidan dan enzim-enzim perbaikan DNA sehingga kerusakan pada DNA lambat diperbaiki atau bahkan tidak dapat diperbaiki. Kondisi inilah yang bisa memicu pembentukan MN (Anderson et al, 2007;Dziaman et al, 2011;Jaishankar et al, 2014;Okocha and Adedeji, 2012;Papanikolaou and Pantopoulos, 2005;Stephenson et al, 2013;Toyokuni, 2009 (Kousar and Javeed, 2015).…”