During the cell cycle, in which phase does Deoxyribonucleic acid (DNA) replication occur?

DNA Replication Occurs in S Phase of the Cell Cycle

DNA replication occurs in the S phase (Synthesis phase) of the cell cycle. This is when the entire genome is duplicated to ensure that each daughter cell receives an identical copy of the genetic material 1.

Cell Cycle Phases and DNA Replication

The cell cycle consists of four main phases:

1. G1 phase (Gap 1):

   • Preparatory phase for DNA synthesis
   • Origin licensing occurs during this phase 2
   • Cell grows in size and synthesizes proteins needed for DNA replication
   • Duration varies depending on cell type

2. S phase (Synthesis):

   • DNA replication occurs during this phase
   • The bulk of RNA:DNA formation occurs during S phase 1
   • Approximately 10% of replication units (replicons) are active at any given time 3
   • Typically lasts about 10 hours in human diploid cells 3

3. G2 phase (Gap 2):

   • Cell continues to grow
   • Prepares for mitosis
   • Checkpoint ensures DNA has been properly replicated

4. M phase (Mitosis):

   • Cell division occurs
   • Duplicated chromosomes are separated into two daughter cells

Molecular Events During S Phase

During S phase, several key molecular events take place:

• DNA polymerases replicate the entire genome
• Replication protein A (RPA) transitions from uniform nuclear distribution to a distinct punctate nuclear pattern 4
• Cyclin A and cdk2 become localized to the nucleus 4
• Sister chromatid cohesion is established during DNA replication 5

Regulation of S Phase Entry and Progression

The transition from G1 to S phase is tightly regulated:

• Phosphorylation of transcriptional inhibitors (RB and pocket family proteins) by cyclin-dependent kinases (CyclinD:Cdk4 and CyclinE:Cdk2) releases them from transcription factors (E2F1-3/DP1-2) 1
• This activation triggers G1-S gene transcription, including genes required for DNA replication 1
• Coordinated origin firing ensures complete and timely chromosome replication 2

Recent Advances in Understanding DNA Replication

While the bulk of DNA replication occurs during S phase, recent evidence suggests that:

• Some parts of the genome may be replicated in G2 or mitosis as a last attempt to ensure complete DNA duplication 6
• Unreplicated gaps may be passed to daughter cells and replicated in the next G1 or S phase 6

These findings challenge the traditional view that DNA replication occurs exclusively during S phase, though the majority of replication still takes place during this period.

Clinical Significance

Understanding the timing of DNA replication is crucial because:

• Defects in DNA replication can compromise genetic integrity and lead to cancer 3
• Cell cycle checkpoints ensure that DNA is properly replicated before cell division
• Many cancer therapies target cells in S phase when they are actively replicating DNA

In conclusion, DNA replication primarily occurs during the S phase of the cell cycle, making option (c) S phase the correct answer.