Rif1 and Exo1 regulate the genomic instability following telomere losses

Area of Science:

• Cellular biology
• Genomics
• Aging research

Background:

• Telomere attrition is associated with aging and diseases like cancer and cardiovascular conditions.
• The mechanisms governing the transition from telomere shortening to profound genomic instability are not well understood.

Purpose of the Study:

• To identify factors regulating cell survival and genomic evolution during telomere attrition.
• To investigate the roles of DNA damage checkpoint proteins, nucleases, Rif1, and Exo1 in yeast cells lacking telomerase.

Main Methods:

• Utilized budding yeast engineered to lack telomerase and other telomere maintenance mechanisms.
• Conducted genetic screening to identify factors influencing cell proliferation and genomic stability during telomere attrition.
• Analyzed the function of specific proteins (Rif1, Exo1) and pathways (DNA damage checkpoints) in survivor cells.

Main Results:

• Initially, DNA damage checkpoint proteins and nucleases (Exo1, Mre11) inhibit proliferation of cells with short telomeres.
• Survivor cells emerging from telomere attrition exhibit checkpoint tolerance to telomere loss while remaining responsive to new DNA damage.
• Rif1 is identified as crucial for checkpoint tolerance and proliferation of telomere-lacking survivors and cells with broken chromosomes.
• Exo1 promotes extensive genomic modifications in survivor cells.

Conclusions:

• The conserved proteins Rif1 and Exo1 play critical, distinct roles in the survival and evolution of cells with lost telomeres.
• Rif1 facilitates adaptation and proliferation in cells experiencing severe genomic instability.
• Exo1 drives the genomic alterations that may contribute to long-term adaptation or malignant transformation.