Abstract
Eukaryotic cells coordinately regulate histone and DNA synthesis. In mammalian cells, most of the regulation of histone synthesis occurs post-transcriptionally by regulating the concentrations of histone mRNA. As cells enter S phase, histone mRNA levels increase, and at the end of S phase they are rapidly degraded. Moreover, inhibition of DNA synthesis causes rapid degradation of histone mRNAs. Replication-dependent histone mRNAs are the only metazoan mRNAs that are not polyadenylated. Instead, they end with a conserved stem-loop structure, which is the only cis-acting element required for coupling regulation of histone mRNA half-life with DNA synthesis. Here we show that regulated degradation of histone mRNAs requires Upf1, a key regulator of the nonsense-mediated decay pathway, and ATR, a key regulator of the DNA damage checkpoint pathway activated during replication stress.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Ataxia Telangiectasia Mutated Proteins
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Caffeine / pharmacology
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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DNA Replication / genetics*
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HeLa Cells
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Histones / genetics*
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Humans
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Hydroxyurea / pharmacology
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Lysine / genetics
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Lysine / metabolism
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Protein Binding / drug effects
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA Helicases
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RNA Stability*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism*
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RNA, Small Interfering / genetics
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Trans-Activators / genetics
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Trans-Activators / metabolism*
Substances
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Cell Cycle Proteins
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Histones
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RNA, Messenger
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RNA, Small Interfering
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Trans-Activators
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Caffeine
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ATR protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases
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RNA Helicases
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UPF1 protein, human
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Lysine
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Hydroxyurea