A role for Mus81 in the repair of chromium-induced DNA damage.
Hexavalent chromium (Cr[VI]) is a toxic environmental contaminant that is capable of producing a broad spectrum of DNA damage. The ability of Cr[VI] to induce mutagenesis and neoplastic transformation has been attributed to its genotoxic action, however our understanding of molecular mechanisms involved in the repair of Cr[VI]-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 Cr[VI]-induced DNA damage. Mus81-deficient cells were found to be more susceptible to Cr[VI]-induced proliferation arrest and more sensitive to the long-term cytotoxic effects of Cr[VI] than isogenic wild-type cells. Following Cr[VI] exposure, Mus81-deficient cells displayed a lag in the disappearance of Rad51 foci, exhibited elevated replication-associated gamma-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 Cr[VI]-DNA lesions into a form more amenable for homologous recombination.
Tamblyn
Laura
L
Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Li
Erica
E
Sarras
Haya
H
Srikanth
Prarthana
P
Hande
M Prakash
MP
McPherson
J Peter
JP
D000818:Animals; D002478:Cells, Cultured; D002857:Chromium / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004720:Endonucleases / Q000235:genetics / Q000502:physiology*; D005434:Flow Cytometry; D007621:Karyotyping; D051379:Mice
D004268:DNA-Binding Proteins; D002857:Chromium; C074702:chromium hexavalent ion; D004720:Endonucleases; C498773:Mus81 protein, mouse