Pathogenic CTC1 mutations cause global genome instabilities under replication stress

Nucleic Acids Research
Yuan Wang, Weihang Chai

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 clo...Continue Reading

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Citations

Oct 4, 2020·Pediatric Dermatology·Francisca MorgadoInês Coutinho
Nov 6, 2018·Molecular Genetics & Genomic Medicine·Forough SargolzaeiavalJunko Oshima
Apr 14, 2019·Life Science Alliance·Yilin WangJason A Stewart
Jul 8, 2020·Genes·Clara Forrer Charlier, Rodrigo A P Martins
Oct 13, 2020·Frontiers in Cell and Developmental Biology·Dinh-Duc NguyenWeihang Chai
Feb 11, 2021·Nature Reviews. Molecular Cell Biology·Ci Ji Lim, Thomas R Cech
Mar 19, 2021·Communications Biology·Joseph M KelichEmmanuel Skordalakes
Mar 30, 2021·DNA Repair·Xinxing LyuWeihang Chai
Nov 7, 2021·Nature Communications·Kai-Hang LeiPeter Chi

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Methods Mentioned

BETA
exome sequencing
co-IP
immunoprecipitation
PCR
ChIP-PCR
ChIP
pull down
ChIP-seq

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