Abstract
The DNA damage response (DDR) is brought about by a protein kinase cascade that orchestrates DNA repair through transcriptional and posttranslational mechanisms. Cell cycle arrest is a hallmark of the DDR. We screened for cells that lacked damage-induced cell cycle arrest and uncovered a critical role for Fanconi anemia and homologous recombination proteins in ATR (ataxia telangiectasia and Rad3-related) signaling. Three DDR candidates, the RNA processing protein INTS7, the circadian transcription factor CLOCK, and a previously uncharacterized protein RHINO, were recruited to sites of DNA damage. RHINO independently bound the Rad9-Rad1-Hus1 complex (9-1-1) and the ATR activator TopBP1. RHINO was recruited to sites of DNA damage by the 9-1-1 complex to promote Chk1 activation. We suggest that RHINO functions together with the 9-1-1 complex and TopBP1 to fully activate ATR.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Ataxia Telangiectasia Mutated Proteins
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Carrier Proteins / metabolism
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Carrier Proteins / physiology*
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Cell Cycle / genetics
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Cell Cycle Proteins / metabolism*
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Cell Line, Tumor
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Chemokines / genetics
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Chemokines / physiology*
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Chemokines, CXC
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DNA Damage
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DNA Repair*
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DNA-Binding Proteins / metabolism
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Exonucleases / metabolism
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Humans
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Multiprotein Complexes / metabolism
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Nuclear Proteins / metabolism
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Protein Serine-Threonine Kinases / metabolism*
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Signal Transduction*
Substances
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CXCL17 protein, human
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Carrier Proteins
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Cell Cycle Proteins
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Chemokines
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Chemokines, CXC
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DNA-Binding Proteins
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HUS1 protein, human
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Multiprotein Complexes
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Nuclear Proteins
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RHNO1 protein, human
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TOPBP1 protein, human
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rad9 protein
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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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Exonucleases
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Rad1 protein, human