Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control

Area of Science:

• Molecular Biology
• Cell Biology
• Genetics

Background:

• DNA replication stress is a significant driver of genomic instability.
• Understanding cellular responses to genotoxic stress is crucial for maintaining genome integrity.

Purpose of the Study:

• To identify factors involved in the DNA replication stress response in Saccharomyces cerevisiae.
• To characterize a novel intranuclear compartment involved in protein quality control under stress.

Main Methods:

• Identification of Cmr1 as a key factor in DNA replication stress response.
• Characterization of the intranuclear quality control (INQ) compartment and its protein components.
• Analysis of the human orthologue WDR76's response to proteasome inhibition and DNA damage.

Main Results:

• Cmr1, along with Mrc1/Claspin, Pph3, CCT, and other proteins, forms the INQ compartment.
• INQ sequesters misfolded, ubiquitylated, and sumoylated proteins in response to genotoxic stress.
• Human WDR76 exhibits similar stress-induced relocalization and CCT association, indicating conserved function.

Conclusions:

• Cmr1/WDR76 plays a role in recovery from genotoxic stress by regulating protein turnover.
• The INQ compartment suggests a broader role in regulating cell cycle, chromatin, and mitotic spindle organization.
• The findings highlight an evolutionarily conserved mechanism for maintaining genomic stability under stress.