Abstract
CTC1 is a component of the mammalian CST (CTC1–STN1–TEN1) complex which plays essential roles in resolving replication problems to facilitate telomeric DNA and genomic DNA replication. We previously reported that the depletion of CTC1 leads to stalled replication fork restart defects. Moreover, the mutation in CTC1 caused cancer-prone diseases including Coats plus (CP) or dyskeratosis congenita (DC). To better understand the CTC1 regulatory axis, the microRNAs (miRNAs) targeting to CTC1 were predicted by a bioinformatics tool, and the selected candidates were further confirmed by a dual-luciferase reporter assay. Here, our current results revealed that miR-376a significantly reduced CTC1 expression at the transcription level by recognizing CTC1 3′-UTR. In addition, the overexpression of miR-376a induced telomere replication defection and resulted in direct replicative telomere damage, which could be rescued by adding back CTC1. Telomere shortening was also observed upon miR-376a treatment. Furthermore, for the clinical patient samples, the high expression of miR-376a was associated with the deregulation of CTC1 and a poor outcome for the rectum adenocarcinoma patients. Together, our results uncovered a novel role of miR-376a in stimulating rectum adenocarcinoma progression via CTC1 downregulating induced telomere dysfunction.
Highlights
Telomere is a tandemly repeated DNA formed at the end of a chromosome and is thought to play essential roles in genomic stability (Turner et al, 2019)
One hundred seven miRNAs were identified to interact with CTC1 messenger RNAs, and these candidates were re-selected by the miRanda program (Betel et al, 2010)
The expressions of these two miRNAs led to telomere replication defects and increased telomere dysfunction-induced foci in several cell lines, exhibiting a CTC1-dependent model which may rely on the ATR signal pathway
Summary
Telomere is a tandemly repeated DNA formed at the end of a chromosome and is thought to play essential roles in genomic stability (Turner et al, 2019). Shelterin is the conserved telomere binding complex consisting of six distinct proteins, including TRF1, TRF2, Rap, TIN2, TPP1, and POT1 (Yin et al, 2014). TRF1 and TRF2 bind to the duplex telomere with high affinity, playing essential roles in telomere replication and protection. POT1 is the single-version component of shelterin that binds to the singlestrand telomeric DNA and functions in telomere protection, G-overhang processing, and telomerase activity regulation. TIN2, and TPP1 connect and stabilize the above three proteins on telomeres (Yin et al, 2014; Liu et al, 2019)
Sign-in/Register to view highlights & summary 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.
