CTC1-STN1 coordinates G- and C-strand synthesis to regulate telomere length

Aging Cell
Peili GuSandy Chang

Abstract

Coats plus (CP) is a rare autosomal recessive disorder caused by mutations in CTC1, a component of the CST (CTC1, STN1, and TEN1) complex important for telomere length maintenance. The molecular basis of how CP mutations impact upon telomere length remains unclear. The CP CTC1L1142H mutation has been previously shown to disrupt telomere maintenance. In this study, we used CRISPR/Cas9 to engineer this mutation into both alleles of HCT116 and RPE cells to demonstrate that CTC1:STN1 interaction is required to repress telomerase activity. CTC1L1142H interacts poorly with STN1, leading to telomerase-mediated telomere elongation. Impaired interaction between CTC1L1142H :STN1 and DNA Pol-α results in increased telomerase recruitment to telomeres and further telomere elongation, revealing that C:S binding to DNA Pol-α is required to fully repress telomerase activity. CP CTC1 mutants that fail to interact with DNA Pol-α resulted in loss of C-strand maintenance and catastrophic telomere shortening. Our findings place the CST complex as an important regulator of both G-strand extensions by telomerase and C-strand synthesis by DNA Pol-α.

References

Sep 1, 1996·Molecular and Cellular Biology·A K Adams, C Holm
Aug 10, 2007·Nature·Eros Lazzerini Denchi, Titia de Lange
Aug 6, 2008·Annual Review of Genetics·Wilhelm Palm, Titia de Lange
Sep 14, 2011·Nucleic Acids Research·Jayakrishnan Nandakumar, Thomas R Cech
Jan 24, 2012·Nature Genetics·Beverley H AndersonYanick J Crow
Apr 26, 2012·Pediatric Blood & Cancer·Rachel B KellerSuneet Agarwal
Jul 6, 2012·Nature·Liuh-Yow ChenJoachim Lingner
Aug 18, 2012·Haematologica·Amanda J WalneInderjeet S Dokal
Sep 12, 2012·Nature Reviews. Genetics·Mary Armanios, Elizabeth H Blackburn
Sep 13, 2013·The Journal of Biological Chemistry·Christopher KasbekCarolyn M Price
Oct 12, 2013·Genes & Development·Liuh-Yow ChenJoachim Lingner
Jul 13, 2016·Genes & Development·Carol W Greider
Nov 4, 2016·Proceedings of the National Academy of Sciences of the United States of America·Kamlesh BishtJayakrishnan Nandakumar
Mar 24, 2017·Nucleic Acids Research·Xuyang FengCarolyn M Price
Sep 22, 2017·Nucleic Acids Research·Swapna Ganduri, Neal F Lue

❮ Previous
Next ❯

Citations

Feb 13, 2019·International Journal of Molecular Sciences·Sergey S ShishkinKsenia Lisitskaya
Mar 21, 2019·British Journal of Haematology·Wenyi ShenJaroslaw P Maciejewski
Oct 31, 2019·The Journal of International Medical Research·Pan LiuLina Ma
Mar 4, 2020·Cancers·Nalini SrinivasRajiv Kumar
Aug 11, 2020·Computational and Structural Biotechnology Journal·Tomas AramburuEmmanuel Skordalakes
Feb 11, 2021·Nature Reviews. Molecular Cell Biology·Ci Ji Lim, Thomas R Cech
Nov 14, 2020·The Journal of Biological Chemistry·Sherilyn Grill, Jayakrishnan Nandakumar
Jan 23, 2021·The Journal of Biological Chemistry·Sherilyn Grill, Jayakrishnan Nandakumar
May 4, 2021·Frontiers in Cell and Developmental Biology·Yang LiuQiang Liu
May 13, 2021·Nature Communications·Richard J ActonChristopher G Bell

❮ Previous
Next ❯

Methods Mentioned

BETA
genotyping
electrophoresis
PCR

Software Mentioned

ImageQuant

Related Concepts

Related Feeds

CRISPR (general)

Clustered regularly interspaced short palindromic repeats (CRISPR) are DNA sequences in the genome that are recognized and cleaved by CRISPR-associated proteins (Cas). CRISPR-Cas system enables the editing of genes to create or correct mutations. Discover the latest research on CRISPR here.

CRISPR for Genome Editing

Genome editing technologies enable the editing of genes to create or correct mutations. Clustered regularly interspaced short palindromic repeats (CRISPR) are DNA sequences in the genome that are recognized and cleaved by CRISPR-associated proteins (Cas). Here is the latest research on the use of CRISPR-Cas system in gene editing.

CRISPR Ribonucleases Deactivation

CRISPR-Cas system enables the editing of genes to create or correct mutations. This feed focuses on mechanisms that underlie deactivation of CRISPR ribonucleases. Here is the latest research.

Cell Aging (Keystone)

This feed focuses on cellular aging with emphasis on the mitochondria, autophagy, and metabolic processes associated with aging and longevity. Here is the latest research on cell aging.

Birth Defects

Birth defects encompass structural and functional alterations that occur during embryonic or fetal development and are present since birth. The cause may be genetic, environmental or unknown and can result in physical and/or mental impairment. Here is the latest research on birth defects.