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  • 1
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    Damage-induced phosphorylation of Sld3 is important to block late origin firing (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-09-25
    Description: Origins of replication are activated throughout the S phase of the cell cycle such that some origins fire early and others fire late to ensure that each chromosome is completely replicated in a timely fashion. However, in response to DNA damage or replication fork stalling, eukaryotic cells block activation of unfired origins. Human cells derived from patients with ataxia telangiectasia are deficient in this process due to the lack of a functional ataxia telangiectasia mutated (ATM) kinase and elicit radioresistant DNA synthesis after gamma-irradiation(2). This effect is conserved in budding yeast, as yeast cells lacking the related kinase Mec1 (ATM and Rad3-related (ATR in humans)) also fail to inhibit DNA synthesis in the presence of DNA damage. This intra-S-phase checkpoint actively regulates DNA synthesis by inhibiting the firing of late replicating origins, and this inhibition requires both Mec1 and the downstream checkpoint kinase Rad53 (Chk2 in humans). However, the Rad53 substrate(s) whose phosphorylation is required to mediate this function has remained unknown. Here we show that the replication initiation protein Sld3 is phosphorylated by Rad53, and that this phosphorylation, along with phosphorylation of the Cdc7 kinase regulatory subunit Dbf4, blocks late origin firing in Saccharomyces cerevisiae. Upon exposure to DNA-damaging agents, cells expressing non-phosphorylatable alleles of SLD3 and DBF4 (SLD3-m25 and dbf4-m25, respectively) proceed through the S phase faster than wild-type cells by inappropriately firing late origins of replication. SLD3-m25 dbf4-m25 cells grow poorly in the presence of the replication inhibitor hydroxyurea and accumulate multiple Rad52 foci. Moreover, SLD3-m25 dbf4-m25 cells are delayed in recovering from transient blocks to replication and subsequently arrest at the DNA damage checkpoint. These data indicate that the intra-S-phase checkpoint functions to block late origin firing in adverse conditions to prevent genomic instability and maximize cell survival.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3393088/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3393088/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lopez-Mosqueda, Jaime -- Maas, Nancy L -- Jonsson, Zophonias O -- Defazio-Eli, Lisa G -- Wohlschlegel, James -- Toczyski, David P -- GM059691/GM/NIGMS NIH HHS/ -- R01 GM059691/GM/NIGMS NIH HHS/ -- R01 GM059691-09/GM/NIGMS NIH HHS/ -- R01 GM059691-10/GM/NIGMS NIH HHS/ -- R01 GM059691-11/GM/NIGMS NIH HHS/ -- R01 GM059691-12/GM/NIGMS NIH HHS/ -- R01 GM089778/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Sep 23;467(7314):479-83. doi: 10.1038/nature09377.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California 94158-9001, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20865002" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Cycle Proteins/genetics/*metabolism ; Checkpoint Kinase 2 ; DNA Damage/*physiology ; DNA Replication/drug effects/*physiology ; DNA-Binding Proteins/deficiency/genetics/*metabolism ; Hydroxyurea/pharmacology ; Phosphorylation/drug effects ; Protein-Serine-Threonine Kinases ; Rad52 DNA Repair and Recombination Protein/metabolism ; Replication Origin/drug effects/*physiology ; *S Phase/drug effects/physiology ; Saccharomyces cerevisiae/cytology/drug effects/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Time Factors
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation (2010)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2010-07-22
    Description: The mammalian adenosine monophosphate-activated protein kinase (AMPK) is a serine-threonine kinase protein complex that is a central regulator of cellular energy homeostasis. However, the mechanisms by which AMPK mediates cellular responses to metabolic stress remain unclear. We found that AMPK activates transcription through direct association with chromatin and phosphorylation of histone H2B at serine 36. AMPK recruitment and H2B Ser36 phosphorylation colocalized within genes activated by AMPK-dependent pathways, both in promoters and in transcribed regions. Ectopic expression of H2B in which Ser36 was substituted by alanine reduced transcription and RNA polymerase II association to AMPK-dependent genes, and lowered cell survival in response to stress. Our results place AMPK-dependent H2B Ser36 phosphorylation in a direct transcriptional and chromatin regulatory pathway leading to cellular adaptation to stress.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3922052/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3922052/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bungard, David -- Fuerth, Benjamin J -- Zeng, Ping-Yao -- Faubert, Brandon -- Maas, Nancy L -- Viollet, Benoit -- Carling, David -- Thompson, Craig B -- Jones, Russell G -- Berger, Shelley L -- CA078831/CA/NCI NIH HHS/ -- CA09171/CA/NCI NIH HHS/ -- CA105463/CA/NCI NIH HHS/ -- MC_U120027537/Medical Research Council/United Kingdom -- MOP-93799/Canadian Institutes of Health Research/Canada -- P01 AG031862/AG/NIA NIH HHS/ -- P01 CA104838/CA/NCI NIH HHS/ -- R01 CA078831/CA/NCI NIH HHS/ -- R01 CA105463/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2010 Sep 3;329(5996):1201-5. doi: 10.1126/science.1191241. Epub 2010 Jul 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Developmental Biology, University of Pennsylvania Medical School, Philadelphia, PA 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20647423" target="_blank"〉PubMed〈/a〉
    Keywords: AMP-Activated Protein Kinases/chemistry/*metabolism ; Adaptation, Physiological ; Amino Acid Motifs ; Amino Acid Substitution ; Animals ; Cell Line ; Cell Line, Tumor ; Cell Survival ; Cells, Cultured ; Chromatin/*metabolism ; Chromatin Immunoprecipitation ; Enzyme Activation ; Gene Expression Regulation ; Histones/chemistry/*metabolism ; Humans ; Mice ; Phosphorylation ; Promoter Regions, Genetic ; Protein-Serine-Threonine Kinases/genetics/metabolism ; Serine/metabolism ; Signal Transduction ; *Stress, Physiological ; *Transcription, Genetic ; Tumor Suppressor Protein p53/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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