CRISPR Screen Reveals Role of Thymidine Metabolism in Telomere Regulation

CRISPR Screen Reveals Role of Thymidine Metabolism in Telomere Regulation

Table of Contents

What are Telomeres?

Telomeres are regions of repetitive DNA sequences at the ends of chromosomes that protect the ends of chromosomes from being frayed, degraded, or tangled. Every time a cell divides, there is a small overhang of DNA that gets degraded – telomeres ensure that it is telomeric DNA that is degraded, not a part of the genome.

This means that telomeres get slightly shorter every time a cell divides. In typical cells, once telomeres become too short for a cell to divide safely, DNA damage machinery triggers the cell to enter senescence or die. In rapidly proliferating cells that divide more frequently, telomere shortening is counteracted by a telomere-lengthening enzyme called telomerase.

How do Telomeres Influence Human Disease?

The delicate balance between telomere shortening, lengthening, and the lifespan of a cell is most commonly focused on in the context of aging and in some rare degenerative conditions. Despite the direct connection between telomere length regulation, lifespan, aging, and certain human diseases, the exact mechanisms of telomere regulation have been unclear.

CRISPR Screen Reveals Role of Thymidine Metabolism in Telomere Regulation

In a recent paper published in Nature Genetics, Mannherz and Agarwal performed a genome-wide CRISPR-Cas9 screen for functional telomere length. Their analysis identified the metabolism of the nucleotide thymidine as a major limiting factor in the maintenance of human telomeres. Deletion of either of two thymidine production genes, TK1 or TYMS, decreased telomere length, while inactivation of a nucleotide degradation enzyme encoded by SAMHD1 lengthened telomeres.

The authors’ findings could have interesting therapeutic applications in genetic telomere disorders, and potentially in aging and healthspan research as well. In vitro, supplementation with thymidine alone increased telomerase activity and telomere length, even in induced pluripotent stem cells derived from patients with genetic telomere disorders. Inhibition of SAMHD1 also promoted telomere restoration in the patient-derived cells. Overall, these findings offer convincing evidence for the central role of thymidine metabolism in the maintenance of human telomere length.

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Jane Cook, Biochemist & Content Writer, Bridge Informatics

Jane Cook, the leading Content Writer for Bridge Informatics, has written over 100 articles on the latest topics and trends for the bioinformatics community. Jane’s broad and deep interdisciplinary molecular biology experience spans developing biochemistry assays to genomics. Prior to joining Bridge, Jane held research assistant roles in biochemistry research labs across a variety of therapeutic areas. While obtaining her B.A. in Biochemistry from Trinity College in Dublin, Ireland, Jane also studied journalism at New York University’s Arthur L. Carter Journalism Institute. As a native Texan, she embraces any challenge that comes her way. Jane hails from Dallas but returns to Ireland any and every chance she gets. If you’re interested in reaching out, please email [email protected] or [email protected].

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