Coordination of DNA damage tolerance mechanisms with cell cycle progression in fission yeast

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• DNA damage tolerance (DDT) mechanisms are crucial for DNA replication fidelity.
• Eukaryotic mutations often arise from mutagenic DDT pathways involving Rev1 and Polζ.
• The coordination of DDT pathways with cell cycle progression remains poorly understood.

Purpose of the Study:

• To investigate the functional coordination of DDT mechanisms throughout the cell cycle.
• To elucidate the interplay between DDT, cell cycle checkpoints, and DNA repair pathways in Schizosaccharomyces pombe.

Main Methods:

• Live-cell imaging techniques were employed.
• The study focused on the fission yeast Schizosaccharomyces pombe.
• Investigated the roles of Rev1, Polζ, Rad51, and homology-directed repair (HDR).

Main Results:

• Checkpoint-dependent mitotic delay promotes high-fidelity DDT via homology-directed repair (HDR).
• Mutagenic DDT polymerases (Rev1 and Polζ) are suppressed during checkpoint delay, dependent on Rad51 recombinase.
• Upon loss of checkpoint control and mitotic entry, HDR capacity is lost, and reliance shifts to mutagenic polymerases.

Conclusions:

• DDT is tightly regulated by cell cycle checkpoints to minimize mutations.
• Mutagenic polymerases are active only during a narrow window when high-fidelity repair is compromised.
• This coordination ensures that mutagenic DNA repair is restricted to specific, vulnerable cell cycle stages.