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

Abstract

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.

Keywords: CST; DNA replication; POT1; chromosome ends; genome integrity; molecular evolution; oxidative damage; protection Of telomeres 1; shelterin; telomerase; telomerase reverse transcriptase (TERT); telomere repeat.

Figure 1.

Model for evolution of telomerase and telomere-associated components from group II retrotransposons and DNA repair proteins. After chromosome linearization by the insertion of group II retrotransposons, telomerase and DNA repair proteins evolved roles in telomere maintenance and end protection. Telomere-associated factors also participate genome-wide in transcription, replication, and repair. Other factors function in mitochondria to modulate the response to oxidative stress. Whether the mitochondrial functions of telomere proteins reflect an ancient or newly evolved function is unknown (see text for details).

Figure 2.

Models for chromosome end protection. Human telomeres are protected by the shelterin complex. CST transiently associates with the telomeric G-overhang during S phase to facilitate replication of the C-rich telomeric strand. In budding yeast, CST provides a stable, protective cap on the G-overhang, and RAP1, a shelterin component ortholog, binds the duplex region of telomeric DNA. Arabidopsis telomeres are asymmetrical. Ku maintains a blunt end on one chromosome terminus, whereas the other end harbors a conventional G-overhang that is bound by CST. There are two functional POT1 paralogs in A. thaliana. AtPOT1a is a component of the telomerase RNP, whereas AtPOT1b promotes genome stability and is proposed to reside in the cytoplasm.

Figure 3.

Diverse functions of POT1. Many POT1 orthologs bind single-stranded G-rich telomeric DNA, serving to control telomere length and to protect chromosome ends from eliciting the DNA damage response. Other POT1 proteins are tailored to engage the telomeric C-strand and its replication machinery. There are also examples of POT1 proteins that do not stably engage the chromosome terminus, but rather function to stimulate telomerase activity or to facilitate DNA repair. In addition, several POT1 proteins have been shown to accumulate in the cytoplasm or are predicted to reside here. Cytoplasmic mouse POT1b (mPOT1b) is proposed to promote an innate immunity response. Shown are the A. thaliana POT1a (AtPOT1a) and POT1b (AtPOT1b); C. elegans POT1 proteins CeOB1, CeOB2, and MRT1; human POT1 (hPOT1), mouse POT1a (mPOT1a), and POT1b (mPOT1b); P. patens POT1 (PpPOT1); and T. thermophila POT1 (TtPOT1) and POT2 (TtPOT2).

Figure 4.

Impact of oxidative stress on telomeres and telomere-associated proteins in mammals. Telomeres are a hot spot for oxidative damage causing base modifications including thymine to thymine glycol and guanine to 8-oxoG. These lesions interfere with DNA binding by TRF1, TRF2, and POT1. These same proteins stimulate BER at telomeres and perhaps elsewhere in the genome, enabling the removal of damaged bases from the DNA. Oxidative DNA damage decreases the abundance of both cytoplasmic and nuclear RAP1, which in turn triggers apoptosis. Conversely, oxidative stress leads to the accumulation in mitochondria of TERT and TIN2, which promote mitochondrial functions that protect against apoptosis.