Cdc5L interacts with ATR and is required for the S-phase cell-cycle checkpoint

Area of Science:

• Molecular Biology
• Cell Biology
• Genetics

Background:

• Cell division cycle 5-like protein (Cdc5L) is a component of a complex involved in pre-messenger RNA splicing.
• Emerging evidence suggests this complex also plays a role in DNA damage response pathways.

Purpose of the Study:

• To investigate the role of Cdc5L in the cellular response to DNA damage.
• To elucidate the interaction between Cdc5L and the ATR kinase pathway.

Main Methods:

• RNA-mediated interference (RNAi) for Cdc5L depletion.
• Analysis of S-phase cell-cycle checkpoint.
• Assessment of cellular sensitivity to replication-fork blocking agents.
• Mapping of the ATR-binding region in Cdc5L.

Main Results:

• Cdc5L physically interacts with ataxia-telangiectasia and Rad3-related (ATR) kinase.
• Cdc5L depletion impairs the S-phase checkpoint and increases sensitivity to DNA damaging agents.
• Cdc5L is essential for activating ATR downstream effectors like Chk1, Rad17, and FancD2.
• A Cdc5L mutant unable to bind ATR is defective in restoring checkpoint function.

Conclusions:

• Cdc5L plays a novel role in regulating the ATR-mediated cell-cycle checkpoint.
• Cdc5L is a key mediator in the DNA damage response pathway, ensuring genomic integrity.