In which phase of the cell cycle does the homologous recombination (HR) apparatus for double-strand break repair have the least or no activity?

Homologous Recombination Activity During Cell Cycle Phases

The G1 phase of the cell cycle has the least or no homologous recombination (HR) apparatus activity for double-strand break repair. 1

Cell Cycle Regulation of Homologous Recombination

Homologous recombination is a DNA repair mechanism that is highly regulated throughout the cell cycle. Understanding when HR is active versus inactive is critical for understanding DNA damage response and genomic stability.

Activity of HR Throughout Cell Cycle Phases:

1. G1 Phase (Least/No Activity):

   • HR is nearly absent during G1 phase 2
   • Cells restrict homologous recombination during G1 3
   • In G1, processing of DNA breaks is inhibited by competition with non-homologous end joining (NHEJ) 4
   • HR is 24-fold lower in G1/G0 compared to S phase 5

2. S Phase (Highest Activity):

   • HR is most active during S phase 2
   • Conservative HR preferentially repairs double-strand breaks in S phase 5
   • DNA replication forks encountering breaks during S phase show most efficient processing 4

3. G2/M Phase (Moderate Activity):

   • HR activity declines in G2/M compared to S phase 2
   • Still more active than in G1 but less than in S phase
   • HR is 39 times lower in M phase compared to S phase 5

4. Prophase of Meiosis I:

   • HR is highly active during prophase of meiosis I (not a phase of minimal activity)
   • Essential for proper chromosome segregation during meiosis

5. S Phase Preceding Meiosis:

   • HR apparatus is active during pre-meiotic S phase
   • Required for subsequent meiotic recombination

Molecular Basis for Cell Cycle Regulation of HR

The regulation of HR activity is controlled by several mechanisms:

• CDK Activity: Cyclin-dependent kinase (CDK) activity is a key regulator of HR, with Clb-CDK activity controlling the resection step 3, 6
• End Resection: The decision between NHEJ and HR is primarily made at the level of DSB end resection 6
• Protein Availability: HR proteins may be absent or inactive outside of S phase 5
• Sister Chromatid Availability: While the presence of sister chromatids facilitates HR, studies show that the regulation occurs even with available homologous templates 5

Clinical Relevance

Understanding the cell cycle dependence of HR has important implications:

• Cancer Therapy: PARP inhibitors exploit synthetic lethality in cells with HR deficiency (HRD) 1
• Diagnostic Testing: Functional assays like RAD51 foci formation specifically examine HR activity during S/G2 phases 1
• Genomic Instability: The preference for error-prone NHEJ over HR in G1 may contribute to genomic instability 2

HR apparatus activity is tightly regulated throughout the cell cycle, with G1 phase showing the least activity, making it the most vulnerable period for accurate repair of double-strand breaks.