The mutagen and carcinogen cadmium is a high-affinity inhibitor of the zinc-dependent MutLα endonuclease

Abstract

SignificanceMutLα (MLH1-PMS2 heterodimer) is an endonuclease that acts during an early step of eukaryotic mismatch repair. We show that human MutLα endonuclease copurifies with two equivalents of bound zinc, at least one of which resides within the endonuclease active site. We also show that cadmium, a known inhibitor of zinc-dependent enzymes and a potent mutagen and carcinogen, is a high-affinity inhibitor of MutLα endonuclease and that exogenous MutLα significantly reverses the mismatch repair defect in cadmium-treated human cell nuclear extract or nuclear extract prepared from cadmium-treated cells. Because the mutagenic action of cadmium is largely due to the selective inhibition of mismatch repair, these findings suggest that MutLα is a primary cadmium target for mutagenesis and presumably, carcinogenesis as well.

Long-range, through-lattice coupling improves predictions of microtubule catastrophe

“…We refined our prior algorithm (Ayaz et al , 2014; Piedra et al , 2016; Mickolajczyk et al , 2018) that used a kinetic Monte Carlo algorithm (Gillespie, 1976; Gibson and Bruck, 2000) to simulate microtubule dynamics. The algorithm simulates one biochemical event (dimer association, dissociation, or GTP hydrolysis) at a time and therefore provides a “movie”’ of microtubule dynamics.…”

“…In these kinds of models, catastrophe and rescue occur naturally (Figure 1C) in a way that depends on the specific parameters used. Our algorithm is constructed in a highly modular way that makes it easy to implement different biochemical assumptions (Piedra et al , 2016; Mickolajczyk et al , 2018). Later in the paper, we relax the minimalistic assumptions of the two-state model to test whether more complicated models that incorporate other states or kinds of biochemistry better predict the concentration dependence of catastrophe.…”

“…Detecting such cooperativity experimentally and determining whether it operates on GTPase and/or the strength of lattice contacts are important challenges for future work. The recently introduced ability to work with tubulins from different species (Drummond et al , 2011; Widlund et al , 2012; Chaaban et al , 2018), to purify single isotypes and site-­directed mutants (Drummond et al , 2011; Johnson et al , 2011; Minoura et al , 2013; Geyer et al , 2015, 2018; Pamula et al , 2016; Ti et al , 2016; Vemu et al , 2016, 2017), and to measure αβ-tubulin:microtubule interactions at the single-molecule level (Mickolajczyk et al , 2018) has the potential to accomplish this, and promises to provide new kinds of data that will drive a deeper understanding of microtubule catastrophe.…”

“…In the present study, we asked whether incorporating various candidates for “missing state/biochemistry” into a computational model would improve predictions about the concentration dependence of microtubule catastrophe. We elaborated a Monte Carlo–based algorithm developed in the lab (Ayaz et al , 2014; Piedra et al , 2016; Mickolajczyk et al , 2018) to test whether incorporating a GDP.P i state or long-range coupling (reflecting conformational accommodation) improved predictions of microtubule catastrophe. We incorporated the GDP.P i state and conformational coupling separately for simplicity and to be able to assess the effect of each change in isolation.…”

Cadmium exposure upregulates SNAIL through miR-30 repression in human lung epithelial cells

“…Earlier studies have identified several molecular processes that are dysregulated by Cd exposure. These include induction of oxidative stress, inhibition of apoptosis and DNA repair process (Sherrer et al, 2018). In addition, dysregulation of epigenetic processes including DNA methylation and histone acetylation causing aberrant gene transcription has been associated with Cd exposure (Park et al, 2017;Peng et al, 2019;Wang and Yang, 2019).…”