Abstract
The human CST complex (CTC1–STN1–TEN1) is associated with telomere functions including genome stability. We have systemically analyzed the sequence of STN and performed structure analysis to establish its association with the Coat Plus (CP) syndrome. Many deleterious non-synonymous SNPs have been identified and subjected for structure analysis to find their pathogenic association and aggregation propensity. A 100-ns all-atom molecular dynamics simulation of WT, R135T, and D157Y structures revealed significant conformational changes in the case of mutants. Changes in hydrogen bonds, secondary structure, and principal component analysis further support the structural basis of STN1 dysfunction in such mutations. Free energy landscape analysis revealed the presence of multiple energy minima, suggesting that R135T and D157Y mutations destabilize and alter the conformational dynamics of STN1 and thus may be associated with the CP syndrome. Our study provides a valuable direction to understand the molecular basis of CP syndrome and offer a newer therapeutics approach to address CP syndrome.
Highlights
Telomere is a complex of protein and nucleic acid, crucial for protecting chromosome ends from degradation, end-to-end chromosome fusion, and activation of DNA damage response (DDR) (de Lange, 2009)
The atomistic levels of two pathogenic mutations (R135T and D157Y) causing Coat Plus (CP) syndrome have been analyzed in detail using all-atom molecular dynamics (MD) simulation approach
We have investigated the effect of deleterious or destabilizing mutations in the STN1 protein that are presumably associated with the CP syndrome
Summary
Telomere is a complex of protein and nucleic acid, crucial for protecting chromosome ends from degradation, end-to-end chromosome fusion, and activation of DNA damage response (DDR) (de Lange, 2009). The CST complex (CTC1–STN1–TEN1) plays a vital role in the synthesis of C-strand of telomere (Chen and Lingner, 2013) and helps in genome-wide replication and recovery from replication fork stalling during replication stress (Stewart et al, 2012, 2018). Interruption of CST complex directly affecting the Mutational Spectrum in STN1 Gene synthesis of C-strand and telomere length leads to the formation of elongated 3′ overhang (Gu et al, 2012)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
