Abstract
The DNA mismatch repair (MMR) pathway is responsible for the repair of base–base mismatches and insertion/deletion loops that arise during DNA replication. MMR deficiency is currently estimated to be present in 15–17% of colorectal cancer cases and 30% of endometrial cancers. MLH1 is one of the key proteins involved in the MMR pathway. Inhibition of a number of mitochondrial genes, including POLG and PINK1 can induce synthetic lethality in MLH1-deficient cells. Here we demonstrate for the first time that loss of MLH1 is associated with a deregulated mitochondrial metabolism, with reduced basal oxygen consumption rate and reduced spare respiratory capacity. Furthermore, MLH1-deficient cells display a significant reduction in activity of the respiratory chain Complex I. As a functional consequence of this perturbed mitochondrial metabolism, MLH1-deficient cells have a reduced anti-oxidant response and show increased sensitivity to reactive oxidative species (ROS)-inducing drugs. Taken together, our results provide evidence for an intrinsic mitochondrial dysfunction in MLH1-deficient cells and a requirement for MLH1 in the regulation of mitochondrial function.
Highlights
When the genes that mediate the DNA mismatch repair (MMR) pathway, such as MLH1, MSH2 and MSH6, are mutated or epigenetically silenced, the predisposition to cancer is vastly increased[1]
Given the dual function of MLH1 in repair of DNA replication errors and mitochondria biogenesis, it is inherently difficult to dissect a separate impact of these two roles upon tumourigenesis
Damage or independently? A number of studies have examined the specific role of oxidative damage repair by the MMR pathway in relation to tumourigenesis
Summary
When the genes that mediate the DNA mismatch repair (MMR) pathway, such as MLH1, MSH2 and MSH6, are mutated or epigenetically silenced, the predisposition to cancer is vastly increased[1]. We further validated our observation by analysing Complex I expression in the MLH1-proficient endometrial cancer cell line KLE, transfected with either Control, non-targeting siRNA or siRNA targeting MLH1 (Fig. 2b; Supplementary Fig. 1B; p < 0.05). We observed a decrease in the activity of Complex I in the MLH1-deficient cell line HCT116, compared to the MLH1 proficient HCT116+ chr[3] cells (Fig. 2d; p < 0.0005).
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