RAD50 phosphorylation promotes ATR downstream signaling and DNA restart following replication stress.
Identifieur interne : 003586 ( Main/Exploration ); précédent : 003585; suivant : 003587RAD50 phosphorylation promotes ATR downstream signaling and DNA restart following replication stress.
Auteurs : Magtouf Gatei [Australie] ; Amanda W. Kijas [Australie] ; Denis Biard [France] ; Thilo Dörk ; Martin F. Lavin [Australie]Source :
- Human molecular genetics [ 1460-2083 ] ; 2014.
Descripteurs français
- KwdFr :
- Ataxie-télangiectasie (anatomopathologie), Cassures double-brin de l'ADN, Checkpoint kinase 1, Enzymes de réparation de l'ADN (métabolisme), Fibroblastes, Humains, Lignée cellulaire, Phosphorylation, Protein kinases (métabolisme), Protéines de liaison à l'ADN (métabolisme), Réplication de l'ADN, Stress physiologique, Sérine (métabolisme), Transduction du signal.
- MESH :
- anatomopathologie : Ataxie-télangiectasie.
- métabolisme : Enzymes de réparation de l'ADN, Protein kinases, Protéines de liaison à l'ADN, Sérine.
- Cassures double-brin de l'ADN, Checkpoint kinase 1, Fibroblastes, Humains, Lignée cellulaire, Phosphorylation, Réplication de l'ADN, Stress physiologique, Transduction du signal.
English descriptors
- KwdEn :
- Ataxia Telangiectasia (pathology), Cell Line, Checkpoint Kinase 1, DNA Breaks, Double-Stranded, DNA Repair Enzymes (metabolism), DNA Replication, DNA-Binding Proteins (metabolism), Fibroblasts, Humans, Phosphorylation, Protein Kinases (metabolism), Serine (metabolism), Signal Transduction, Stress, Physiological.
- MESH :
- chemical , metabolism : DNA Repair Enzymes, DNA-Binding Proteins, Protein Kinases, Serine.
- chemical : Checkpoint Kinase 1.
- pathology : Ataxia Telangiectasia.
- Cell Line, DNA Breaks, Double-Stranded, DNA Replication, Fibroblasts, Humans, Phosphorylation, Signal Transduction, Stress, Physiological.
Abstract
The MRE11/RAD50/NBN (MRN) complex plays a key role in detecting DNA double-strand breaks, recruiting and activating ataxia-telangiectasia mutated and in processing the breaks. Members of this complex also act as adaptor molecules for downstream signaling to the cell cycle and other cellular processes. Somewhat more controversial are the results to support a role for MRN in the ataxia-telangiectasia and Rad3-related (ATR) activation and signaling. We provide evidence that RAD50 is required for ATR activation in mammalian cells in response to DNA replication stress. It is in turn phosphorylated at a specific site (S635) by ATR, which is required for ATR signaling through Chk1 and other downstream substrates. We find that RAD50 phosphorylation is essential for DNA replication restart by promoting loading of cohesin at these sites. We also demonstrate that replication stress-induced RAD50 phosphorylation is functionally significant for cell survival and cell cycle checkpoint activation. These results highlight the importance of the adaptor role for a member of the MRN complex in all aspects of the response to DNA replication stress.
DOI: 10.1093/hmg/ddu141
PubMed: 24694934
Affiliations:
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Le document en format XML
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<term>DNA Breaks, Double-Stranded</term>
<term>DNA Repair Enzymes (metabolism)</term>
<term>DNA Replication</term>
<term>DNA-Binding Proteins (metabolism)</term>
<term>Fibroblasts</term>
<term>Humans</term>
<term>Phosphorylation</term>
<term>Protein Kinases (metabolism)</term>
<term>Serine (metabolism)</term>
<term>Signal Transduction</term>
<term>Stress, Physiological</term>
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<term>Cassures double-brin de l'ADN</term>
<term>Checkpoint kinase 1</term>
<term>Enzymes de réparation de l'ADN (métabolisme)</term>
<term>Fibroblastes</term>
<term>Humains</term>
<term>Lignée cellulaire</term>
<term>Phosphorylation</term>
<term>Protein kinases (métabolisme)</term>
<term>Protéines de liaison à l'ADN (métabolisme)</term>
<term>Réplication de l'ADN</term>
<term>Stress physiologique</term>
<term>Sérine (métabolisme)</term>
<term>Transduction du signal</term>
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<term>DNA-Binding Proteins</term>
<term>Protein Kinases</term>
<term>Serine</term>
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<term>Protein kinases</term>
<term>Protéines de liaison à l'ADN</term>
<term>Sérine</term>
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<term>DNA Breaks, Double-Stranded</term>
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<term>Fibroblasts</term>
<term>Humans</term>
<term>Phosphorylation</term>
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<term>Humains</term>
<term>Lignée cellulaire</term>
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<front><div type="abstract" xml:lang="en">The MRE11/RAD50/NBN (MRN) complex plays a key role in detecting DNA double-strand breaks, recruiting and activating ataxia-telangiectasia mutated and in processing the breaks. Members of this complex also act as adaptor molecules for downstream signaling to the cell cycle and other cellular processes. Somewhat more controversial are the results to support a role for MRN in the ataxia-telangiectasia and Rad3-related (ATR) activation and signaling. We provide evidence that RAD50 is required for ATR activation in mammalian cells in response to DNA replication stress. It is in turn phosphorylated at a specific site (S635) by ATR, which is required for ATR signaling through Chk1 and other downstream substrates. We find that RAD50 phosphorylation is essential for DNA replication restart by promoting loading of cohesin at these sites. We also demonstrate that replication stress-induced RAD50 phosphorylation is functionally significant for cell survival and cell cycle checkpoint activation. These results highlight the importance of the adaptor role for a member of the MRN complex in all aspects of the response to DNA replication stress.</div>
</front>
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