Werner syndrome protein, WRN, protects cells from DNA damage induced by the benzene metabolite hydroquinone.
Werner syndrome (WS) is a rare autosomal progeroid disorder caused by a mutation in the gene encoding the WRN (Werner syndrome protein), a member of the RecQ family of helicases with a role in maintaining genomic stability. Genetic association studies have previously suggested a link between WRN and susceptibility to benzene-induced hematotoxicity. To further explore the role of WRN in benzene-induced hematotoxicity, we used short hairpin RNA to silence endogenous levels of WRN in the human HL60 acute promyelocytic cell line and subsequently exposed the cells to hydroquinone (HQ). Suppression of WRN led to an accelerated cell growth rate, increased susceptibility to hydroquinone-induced cytotoxicity and genotoxicity as measured by the single-cell gel electrophoresis assay, and an enhanced DNA damage response. More specifically, loss of WRN resulted in higher levels of early apoptosis, marked by increases in relative levels of cleaved caspase-7 and cleaved poly (ADP-ribose) polymerase 1, in cells treated with HQ compared with control cells. Our data suggests that WRN plays an important role in the surveillance of and protection against DNA damage induced by HQ. This provides mechanistic support for the link between WRN and benzene-induced hematotoxicity.
Ren
Xuefeng
X
Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, California 94720, USA.
Lim
Sophia
S
Smith
Martyn T
MT
Zhang
Luoping
L
D017209:Apoptosis / Q000187:drug effects; D001554:Benzene / Q000378:metabolism*; D015153:Blotting, Western; D053179:Caspase 7 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005090:Exodeoxyribonucleases / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D006873:Hydroquinones / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D008968:Molecular Conformation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000737:chemistry; D053484:RecQ Helicases / Q000494:pharmacology*; D012190:Retroviridae / Q000235:genetics; D014898:Werner Syndrome / Q000378:metabolism*; D000071657:Werner Syndrome Helicase
D006873:Hydroquinones; D012313:RNA; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D005090:Exodeoxyribonucleases; D053179:Caspase 7; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; D001554:Benzene