A role for Mus81 in the repair of chromium-induced DNA damage

Hexavalent chromium (CrVI]) is a toxic environmental contaminant that is capable of producing a broad spectrum of DNA damage. The ability of CrVI] to induce mutagenesis and neoplastic transformation has been attributed to its genotoxic action, however our understanding of molecular mechanisms involved in the repair of CrVI]-induced DNA damage remains incomplete. Here, we report that Mus81, an enzyme that participates with Eme1 in the resolution of replication fork damage caused by certain lesions, is involved in the repair of CrVI]-induced DNA damage. Mus81-deficient cells were found to be more susceptible to CrVI]-induced proliferation arrest and more sensitive to the long-term cytotoxic effects of CrVI] than isogenic wild-type cells. Following CrVI] exposure, Mus81-deficient cells displayed a lag in the disappearance of Rad51 foci, exhibited elevated replication-associated γ-H2AX and showed an increased incidence of chromosomal instability compared to wild-type cells. Our findings support a role for Mus81 in the resolution of replication-associated DNA damage associated with this genotoxic agent, by converting CrVI]-DNA lesions into a form more amenable for homologous recombination.