Pathogenic CTC1 mutations cause global genome instabilities under replication stress.

Area of Science:

• Genetics
• Molecular Biology
• Cell Biology

Background:

• Coats plus syndrome is a genetic disorder linked to mutations in the CTC1-STN1-TEN1 (CST) complex.
• Previous research suggested Coats plus arises from telomere dysfunction due to CST complex defects.
• Emerging evidence highlights the CST complex's role in managing replication stress and stabilizing fragile genomic sites.

Purpose of the Study:

• To investigate how disease-causing CTC1 mutations affect genome stability.
• To determine if genomic instabilities contribute to Coats plus pathology.
• To elucidate the molecular mechanisms underlying CTC1's role in genome maintenance.

Main Methods:

• Characterization of eleven disease-causing CTC1 missense and small deletion mutations.
• Assessment of chromosome breakage, fragmentation, and global genome instability.
• Analysis of CST complex interaction with RAD51 and binding to GC-rich fragile sites.
• Evaluation of cell proliferation and clonal viability under stressed and unstressed conditions.

Main Results:

• CTC1 mutations induce spontaneous chromosome breakage and fragmentation, exacerbated by replication stress.
• These mutations impair the interaction between the CST complex and RAD51, disrupting RAD51 foci formation.
• Mutations reduce CST binding to GC-rich fragile sites and limit cell proliferation and viability, especially under replication stress.
• A RAD51-interacting domain was identified within the CTC1 aa 600-989 region.

Conclusions:

• Replication-associated genomic defects, including chromosome instability and impaired DNA repair, are molecularly linked to Coats plus syndrome.
• The CST complex, through its interaction with RAD51 and stabilization of fragile sites, is crucial for maintaining genome integrity.
• Understanding these mechanisms provides new insights into the pathogenesis of Coats plus syndrome.