Back to the future: The intimate and evolving connection between telomere-related factors and genotoxic stress

Abstract

Edited by Patrick Sung The conversion of circular genomes to linear chromosomes during molecular evolution required the invention of telomeres. This entailed the acquisition of factors necessary to fulfill two new requirements: the need to fully replicate terminal DNA sequences and the ability to distinguish chromosome ends from damaged DNA. Here we consider the multifaceted functions of factors recruited to perpetuate and stabilize telomeres. We discuss recent theories for how telomere factors evolved from existing cellular machineries and examine their engagement in nontelomeric functions such as DNA repair, replication, and transcriptional regulation. We highlight the remarkable versatility of protection of telomeres 1 (POT1) proteins that was fueled by gene duplication and divergence events that occurred independently across several eukaryotic lineages. Finally, we consider the relationship between oxidative stress and telomeres and the enigmatic role of telomere-associated proteins in mitochondria. These findings point to an evolving and intimate connection between telomeres and cellular physiology and the strong drive to maintain chromosome integrity.

A Nested PCR Telomere Fusion Assay Highlights the Widespread End-Capping Protection of Arabidopsis CTC1

“…It has been previously proposed that whereas CTC1 and the CST complex cap all Arabidopsis chromosome ends containing 3′ overhangs, the KU70/KU80 heterodimer caps the blunt-ended telomeres [ 14 ]. However, FISH and PCR analyses have shown that the loss of KU70 or KU80 does not lead to telomere fusions, which should reflect the presence of additional capping mechanisms at blunt-ended telomeres [ 9 , 11 , 12 , 13 , 14 ]. Our results are in agreement with this proposal because they support the widespread end-capping protection achieved by CTC1.…”

“…Therefore, the KU70/KU80 heterodimer also protects Arabidopsis telomeres. However, it does not protect them against inter-telomeric recombination events leading to telomere fusions [ 9 , 11 , 12 , 13 , 14 ]. Thus, the KU70/KU80 heterodimer protects telomeres differently in mammals and plants.…”

Arabidopsis AN3 and OLIGOCELLULA genes link telomere maintenance mechanisms with cell division and expansion control

“…Much attention has recently been given to the non-canonical functions of telomerase and telomere-associated factors in DNA repair, transcription and cell cycle control ( Barbero Barcenilla B, Shippen, 2019 ; Hong et al 2016 ; Valeeva et al 2023 ). Conversely, multiple lines of evidence from different eukaryotic systems indicate that many developmental and cellular pathways beyond the classical telomere biology genes also have pleiotropic impacts on telomere length regulation.…”

Getting to grips with circular chromosomes

“…One of the most widely studied capping molecules is a protein called Cdc13 that binds to certain types of single-stranded DNA in budding yeast, and forms a complex with two other proteins (Stn1 and Ten1) that recruits telomerase ( Wellinger and Zakian, 2012 ). Several lines of evidence suggest that this CST complex also recruits a DNA replication enzyme called primase-Polα, and can regulate the activity of this enzyme at the ends of chromosomes as well as other locations in the genome ( Giraud-Panis et al, 2010 ; Price et al, 2010 ; Barbero Barcenilla and Shippen, 2019 ).…”