Metabolic remodeling maintains a reducing environment for rapid activation of the yeast DNA replication checkpoint.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Wiley Blackwell Country of Publication: England NLM ID: 8208664 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-2075 (Electronic) Linking ISSN: 02614189 NLM ISO Abbreviation: EMBO J Subsets: MEDLINE
    • Publication Information:
      Publication: 2014- : London : Wiley Blackwell
      Original Publication: Eynsham, Oxford, England : Published for the European Molecular Biology Organization by IRL Press, [c1982-
    • Subject Terms:
      DNA Replication*/drug effects; Protein Serine-Threonine Kinases/*metabolism ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae/*metabolism; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Checkpoint Kinase 2/genetics ; Checkpoint Kinase 2/metabolism ; DNA, Single-Stranded/metabolism ; Glucose/genetics ; Glucose/metabolism ; Glycolysis/physiology ; Hydroxyurea ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; NADP/metabolism ; Pentose Phosphate Pathway ; Phosphorylation ; Protein Serine-Threonine Kinases/genetics ; Replication Protein A/genetics ; Replication Protein A/metabolism ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Saccharomyces cerevisiae/drug effects ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism
    • Abstract:
      Nucleotide metabolism fuels normal DNA replication and is also primarily targeted by the DNA replication checkpoint when replication stalls. To reveal a comprehensive interconnection between genome maintenance and metabolism, we analyzed the metabolomic changes upon replication stress in the budding yeast S. cerevisiae. We found that upon treatment of cells with hydroxyurea, glucose is rapidly diverted to the oxidative pentose phosphate pathway (PPP). This effect is mediated by the AMP-dependent kinase, SNF1, which phosphorylates the transcription factor Mig1, thereby relieving repression of the gene encoding the rate-limiting enzyme of the PPP. Surprisingly, NADPH produced by the PPP is required for efficient recruitment of replication protein A (RPA) to single-stranded DNA, providing the signal for the activation of the Mec1/ATR-Rad53/CHK1 checkpoint signaling kinase cascade. Thus, SNF1, best known as a central energy controller, determines a fast mode of replication checkpoint activation through a redox mechanism. These findings establish that SNF1 provides a hub with direct links to cellular metabolism, redox, and surveillance of DNA replication in eukaryotes.
      (© 2022 The Authors.)
    • References:
      Cell. 1998 Sep 4;94(5):595-605. (PMID: 9741624)
      Nat Commun. 2019 Jun 7;10(1):2502. (PMID: 31175280)
      Bioinformatics. 2014 Aug 1;30(15):2114-20. (PMID: 24695404)
      Bioinformatics. 2017 Jun 9;33(19):3137-3139. (PMID: 28605449)
      J Biol Chem. 2014 May 2;289(18):12863-75. (PMID: 24627493)
      Cell Rep. 2017 Oct 3;21(1):1-9. (PMID: 28978464)
      BMC Biotechnol. 2016 Apr 01;16:31. (PMID: 27036139)
      J Biol Chem. 1999 Oct 8;274(41):29075-80. (PMID: 10506160)
      Mol Cell. 2017 Oct 19;68(2):431-445.e5. (PMID: 29033322)
      Nat Cell Biol. 2014 Jan;16(1):2-9. (PMID: 24366029)
      EMBO J. 2022 Feb 15;41(4):e108290. (PMID: 35028974)
      FEBS Lett. 1999 Jun 18;453(1-2):219-23. (PMID: 10403407)
      Front Biosci. 2008 Jan 01;13:2408-20. (PMID: 17981722)
      Nat Rev Mol Cell Biol. 2019 Jul;20(7):436-450. (PMID: 30976106)
      PLoS Genet. 2019 Aug 5;15(8):e1008136. (PMID: 31381575)
      EMBO J. 2001 Jul 2;20(13):3544-53. (PMID: 11432841)
      Antioxid Redox Signal. 2001 Aug;3(4):657-69. (PMID: 11554452)
      J Cell Sci. 2015 Dec 1;128(23):4255-62. (PMID: 26567218)
      Nucleic Acids Res. 2016 Jul 8;44(W1):W160-5. (PMID: 27079975)
      Clin Transl Oncol. 2018 Sep;20(9):1145-1152. (PMID: 29340974)
      Genetics. 1992 Nov;132(3):639-50. (PMID: 1468623)
      Mol Cell. 2017 Jun 15;66(6):801-817. (PMID: 28622525)
      Genes (Basel). 2016 Nov 17;7(11):. (PMID: 27869662)
      Nat Rev Cancer. 2015 Mar;15(3):166-80. (PMID: 25709118)
      Prog Biophys Mol Biol. 2001 Nov;77(3):177-268. (PMID: 11796141)
      Science. 2007 Jun 29;316(5833):1916-9. (PMID: 17600220)
      Science. 2010 Oct 22;330(6003):517-21. (PMID: 20966255)
      Redox Biol. 2019 Jul;25:101154. (PMID: 30853530)
      Mol Cell. 2009 Dec 11;36(5):845-60. (PMID: 20005847)
      Front Microbiol. 2018 Jan 25;9:47. (PMID: 29422886)
      Nature. 2010 Sep 23;467(7314):474-8. (PMID: 20835227)
      Curr Biol. 1996 Nov 1;6(11):1426-34. (PMID: 8939604)
      Proc Natl Acad Sci U S A. 2010 Aug 3;107(31):13660-5. (PMID: 20616048)
      Genes Dev. 1998 Sep 15;12(18):2956-70. (PMID: 9744871)
      Nat Rev Mol Cell Biol. 2017 Oct;18(10):622-636. (PMID: 28811666)
      Biochim Biophys Acta. 2013 Dec;1833(12):3254-3264. (PMID: 24084603)
      Nat Rev Mol Cell Biol. 2020 Oct;21(10):633-651. (PMID: 32612242)
      Nature. 2012 May 09;485(7400):661-5. (PMID: 22660331)
      Sci Rep. 2016 Jul 11;6:29361. (PMID: 27405729)
      Yeast. 2008 Oct;25(10):745-54. (PMID: 18949820)
      Annu Rev Nutr. 2014;34:31-55. (PMID: 24850385)
      Cell Cycle. 2010 Jun 1;9(11):2189-200. (PMID: 20505334)
      DNA Repair (Amst). 2009 Sep 2;8(9):996-1003. (PMID: 19464966)
      Annu Rev Genet. 2016 Nov 23;50:155-173. (PMID: 27617969)
      Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):2554-9. (PMID: 24550282)
      Genome Biol. 2012 Mar 16;13(3):R16. (PMID: 22424423)
      Mol Cell. 1998 Sep;2(3):329-40. (PMID: 9774971)
      Annu Rev Biochem. 1997;66:61-92. (PMID: 9242902)
      Mol Cell. 2016 Dec 1;64(5):951-966. (PMID: 27889450)
      Dev Cell. 2017 Apr 10;41(1):59-71.e4. (PMID: 28399401)
      Genome Biol. 2008;9(9):R137. (PMID: 18798982)
      Nat Methods. 2012 Mar 04;9(4):357-9. (PMID: 22388286)
      Cell Mol Life Sci. 2017 Jul;74(13):2361-2380. (PMID: 28220209)
      Genes (Basel). 2013 Aug 19;4(3):388-434. (PMID: 24705211)
      EMBO J. 2019 Sep 16;38(18):e101801. (PMID: 31393028)
      EMBO J. 2018 Sep 3;37(17):. (PMID: 30065069)
      Science. 2017 Jan 27;355(6323):415-420. (PMID: 28126821)
      Mol Cell Biol. 2004 Mar;24(6):2560-72. (PMID: 14993292)
      Mol Cell. 2010 Oct 22;40(2):179-204. (PMID: 20965415)
      Cell Rep. 2015 Dec 22;13(11):2576-2586. (PMID: 26686640)
      EMBO J. 2009 Apr 22;28(8):1142-56. (PMID: 19279665)
      Cold Spring Harb Perspect Biol. 2013 Sep 01;5(9):. (PMID: 24003211)
      J Biol Chem. 2000 Sep 1;275(35):27332-8. (PMID: 10856290)
      FEMS Yeast Res. 2017 Mar 1;17(2):. (PMID: 27915243)
      Bioinformatics. 2009 Aug 15;25(16):2078-9. (PMID: 19505943)
      Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3132-6. (PMID: 7724528)
      Mol Cell Biol. 1998 Nov;18(11):6273-80. (PMID: 9774644)
      Proc Natl Acad Sci U S A. 2020 Apr 7;117(14):7575-7583. (PMID: 32213592)
      Nat Cell Biol. 2001 Nov;3(11):958-65. (PMID: 11715016)
    • Contributed Indexing:
      Keywords: DNA replication stress; carbon metabolism; cell cycle checkpoints; genome stability; reductive/oxidative (redox)
    • Accession Number:
      0 (CYC8 protein, S cerevisiae)
      0 (Cell Cycle Proteins)
      0 (DNA, Single-Stranded)
      0 (Intracellular Signaling Peptides and Proteins)
      0 (MIG1 protein, S cerevisiae)
      0 (Replication Protein A)
      0 (Repressor Proteins)
      0 (Saccharomyces cerevisiae Proteins)
      53-59-8 (NADP)
      EC 2.7.1.- (SNF1-related protein kinases)
      EC 2.7.1.11 (Checkpoint Kinase 2)
      EC 2.7.11.1 (MEC1 protein, S cerevisiae)
      EC 2.7.11.1 (Protein Serine-Threonine Kinases)
      EC 2.7.12.1 (RAD53 protein, S cerevisiae)
      IY9XDZ35W2 (Glucose)
      X6Q56QN5QC (Hydroxyurea)
    • Publication Date:
      Date Created: 20220114 Date Completed: 20220308 Latest Revision: 20230217
    • Publication Date:
      20230217
    • Accession Number:
      PMC8844976
    • Accession Number:
      10.15252/embj.2021108290
    • Accession Number:
      35028974