Pathogenic CTC1 mutations cause global genome instabilities under replication stress.

Abstract

Coats plus syndrome is a complex genetic disorder that can be caused by mutations in genes encoding the CTC1-STN1-TEN1 (CST) complex, a conserved single-stranded DNA binding protein complex. Studies have demonstrated that mutations identified in Coats plus patients are defective in telomere maintenance, and concluded that Coats plus may be caused by telomere dysfunction. Recent studies have established that CST also plays an important role in countering replication stress and protecting the stability of genomic fragile sites. However, it is unclear whether instabilities at genomic regions may promote Coats plus development. Here, we characterize eleven reported disease-causing CTC1 missense and small deletion mutations in maintaining genome stability. Our results show that these mutations induce spontaneous chromosome breakage and severe chromosome fragmentation that are further elevated by replication stress, leading to global genome instabilities. These mutations abolish or reduce CST interaction with RAD51, disrupt RAD51 foci formation, and/or diminish binding to GC-rich genomic fragile sites under replication stress. Furthermore, CTC1 mutations limit cell proliferation under unstressed condition and significantly reduce clonal viability under replication stress. Results also suggest that the aa 600-989 region of CTC1 contains a RAD51-interacting domain. Our findings thus provide molecular evidence linking replication-associated genomic defects with CP disease pathology.

• Authors: Yuan Wang, Weihang Chai
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 46 Issue 8 Pg. 3981-3992 (05 04 2018) ISSN: 1362-4962 [Electronic] England
• PMID: 29481669 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Ctc1 protein, human
• Telomere-Binding Proteins
• RAD51 protein, human
• Rad51 Recombinase

Topics

• Ataxia (genetics)
• Brain Neoplasms (genetics)
• Calcinosis (genetics)
• Cell Proliferation
• Central Nervous System Cysts (genetics)
• DNA Replication
• Genomic Instability
• HEK293 Cells
• HeLa Cells
• Humans
• Leukoencephalopathies (genetics)
• Muscle Spasticity (genetics)
• Mutation
• Rad51 Recombinase (metabolism)
• Retinal Diseases (genetics)
• Seizures (genetics)
• Stress, Physiological (genetics)
• Telomere-Binding Proteins (chemistry, genetics, metabolism)