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S-phase checkpoint regulations that preserve replication and chromosome integrity upon dNTP depletion

Michele Giannattasio1,2, Dana Branzei3

  • 1Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Via Adamello 16, 20139, Milan, Italy. michele.giannattasio@ifom.eu.

Cellular and Molecular Life Sciences : CMLS
|February 22, 2017
PubMed

Insights

DNA replication stress, caused by low deoxynucleotide triphosphates (dNTPs), can lead to genomic instability. The S-phase checkpoint protects DNA replication forks and genome integrity during these stressful conditions.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • DNA replication stress is a major cause of genomic instability.
  • Replication fork stalling occurs due to various DNA replication perturbations.
  • Deoxynucleotide triphosphate (dNTP) pool depletion slows DNA synthesis genome-wide.

Purpose of the Study:

  • To review the functions of the replication checkpoint in maintaining genome integrity.
  • To summarize mechanisms that stabilize stalled replication forks under dNTP depletion.
  • To highlight the role of the S-phase checkpoint in preventing chromosome fragmentation.

Main Methods:

  • This review synthesizes existing research on DNA replication stress and the S-phase checkpoint.
  • It examines pathways regulating ribonucleotide reductase activity.
  • It analyzes the temporal program of origin firing and cell cycle transitions.

Main Results:

  • The S-phase checkpoint is crucial for preserving stalled replication fork functionality and structure.
  • Extrinsic pathways, including dNTP pool regulation and origin firing, are involved.
  • The checkpoint also modulates replisome components to ensure replication integrity.

Conclusions:

  • The S-phase checkpoint is essential for maintaining genome integrity during replication stress.
  • It employs both extrinsic and intrinsic mechanisms to protect stalled replication forks.
  • Understanding these pathways is vital for addressing genomic instability.
Keywords:
ATR/Mec1/Rad3Chromosome fragilityFork remodelingHelicasesNucleasesRad53/CHK1/Cds1Stalled replication forks

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