Figures (2)  Tables (2)

    • Figure 1. 

      DNA replication is coordinated with cell metabolism. (1) Biosynthetic demand: the biosynthesis of macromolecules is important for DNA replication. In particular, dNTP, including dTTP, dCTP, dGTP, and dATP, which serve as basic building blocks, are much in demand; (2) Bioenergetic demand: energy supply is also indispensable for DNA replication. For instance, changes in ATP level can affect DNA replication; (3) Redox homeostasis: hydrogen peroxide (H2O2), hydroxyl radical (·OH), and superoxide anion (·O2−) that are the main resources of ROS can influence DNA replication in different manners.

    • Figure 2. 

      Metabolic regulation of DNA replication. (1) Metabolic intermediates: small molecules, such as acetyl-CoA, ATP, SAM, and UDP-GlcNAc, function as donors and support the establishment of PTMs on key factors to regulate DNA replication; (2) Metabolic enzymes: classic enzymes that control metabolic reactions may enter the nucleus and regulate fork function/stability directly.

    • Protein Site(s) Function Ref.
      Replisome components MCM2-7 Unknown Promotes MCMs loading on chromatin [87]
      FEN1 S352 Disrupts FEN1 interaction with PCNA, causing replication defect and DNA damage [93]
      AND-1 S575, S893 Promotes HR to protect genome stability [94]
      Histones H4 S47 Directs DDK recruitment to promote replication origin activation [83]
      H2A S40 Associate with γH2AX to promote genome stability [84]
      DNA damage repair factors PLK1 T291 Required for proper chromosome segregation and thus important for the maintenance of genome stability [98]
      H2AX S139 Antagonizes phosphorylation of S139 on H2AX to restrain DNA damage signaling and protect genome integrity [90]
      Polη T457 Promotes TLS synthesis [99]
      MRE11 Unknown Promotes MRE11 recruitment on chromatin to protect genome integrity [100]
      RPA2 S4, S8 Antagonizes RPA2 S4/8 phosphorylation and impairs Chk1 activation [89]
      MCM, minichromosome maintenance; FEN1, flap endonuclease 1; AND-1, acidic nucleoplasmic DNA-binding protein 1; PLK1, polo-like kinase 1; Polη, DNA polymerase eta; MRE11, meiotic recombination 11; RPA, replication protein A; HR, homologous recombination.

      Table 1. 

      O-GlcNAcylation on factors that are potentially involved in the control of DNA replication.

    • Metabolic enzyme Function in DNA replication Ref.
      PGK1 Binds to CDC7 and convert ADP to ATP for origin activation [12]
      PRDX2 Associates with TIMELESS-TIPIN at the replication fork to adjust fork speed [11]
      OGT Enriches on chromatin in S phase and modifies H4 S47 to promote origin activation [83]
      ACO2 Knockdown of ACO2 compromises DNA synthesis [94]
      HK2 Knockdown of HK2 compromises DNA synthesis [94]
      GAPDH Knockdown of GAPDH compromises DNA synthesis [94]
      PDC Localizes in the nucleus and regulates S phase entry [97]
      H6PD Knockdown of H6PD impairs DNA synthesis [93]
      RPE Knockdown of RPE impairs DNA synthesis [93]
      PRPS1 Knockdown of PRPS1 impairs DNA synthesis [93]
      ACLY Regulates nuclear acetyl-CoA concentration thereby regulating MCM2-7 and CDC45 transcription [101]
      FH Knockout of FH in S. cerevisiae leads to be sensitive to HU [95]
      IDH1/2 IDH1/2 mutants regulate DNA replication by contributing heterochromatin formation [96]
      PGK1, phosphoglycerate kinase 1; PRDX2, peroxiredoxin 2; OGT, O-GlcNAc transferase; ACO2, aconitate hydratase 2; HK2, hexokinase 2; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PDC, pyruvate dehydrogenase complex; H6PD, hexose-6-phosphate dehydrogenase; RPE, ribulose 5-phosphate epimerase; PRPS1, ribose-phosphate pyrophosphokinase 1; ACLY, ATP-citrate lyase; FH, fumarate hydratase; IDH, isocitrate dehydrogenase.

      Table 2. 

      Metabolic enzymes potentially involved in the regulation of DNA replication.