Nitric oxide upregulates expression of DNA-PKcs to protect cells from DNA-damaging anti-tumour agents.
Nitric-oxide synthase (NOS) activity has been detected in many human tumours, although its function is unclear. Here we show that exposure of cells to nitric oxide (NO) results in a 4-5-fold increase in expression of the DNA-dependent protein-kinase catalytic subunit (DNA-PKcs), one of the key enzymes involved in repairing double-stranded DNA breaks. This NO-mediated increase in enzymatically active DNA-PK not only protects cells from the toxic effects of NO, but also provides crossprotection against clinically important DNA-damaging agents, such as X-ray radiation, adriamycin, bleomycin and cisplatin. The NO-mediated increase in DNA-PKcs described here demonstrates the presence of a new and highly effective NO-mediated mechanism for DNA repair.
Xu
W
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The Wolfson Institute for Biomedical Research, The Cruciform Building, University College London, Gower Street, London WC1E 6BT, UK.
Liu
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Smith
G C
GC
Charles
l G
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D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology; D020134:Catalytic Domain; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D004317:Doxorubicin / Q000494:pharmacology; D004441:Ecdysterone / Q000031:analogs & derivatives / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism* / Q000633:toxicity; D020030:Nitric Oxide Donors / Q000378:metabolism / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D020030:Nitric Oxide Donors; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D001761:Bleomycin; D009569:Nitric Oxide; C055348:muristerone A; D004441:Ecdysterone; D004317:Doxorubicin; D004247:DNA; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; D002945:Cisplatin