A loopy view of telomere evolution

Abstract

About a decade ago, I proposed that t-loops, the lariat structures adopted by many eukaryotic telomeres, could explain how the transition from circular to linear chromosomes was successfully negotiated by early eukaryotes. Here I reconsider this loopy hypothesis in the context of the idea that eukaryotes evolved through a period of genome invasion by Group II introns.

Keywords: DNA damage; Group II intron; eukaryote; replication; telomerase; telomere.

FIGURE 1

Modern telomeres and their proposed t-loop precursor. (A) Current telomeres require a telomerase that synthesizes the telomeric repeats and counteracts the end-replication problem. They also require telomere specific proteins that recognize the telomerase products at chromosome ends and protect the ends from the DNA damage response (solving the end-protection problem). (B) Mammalian telomeres form t-loops, which sequester the telomere end and prevent ligation by NHEJ. Telomeric proteins (blue, e.g., TRF2) are needed to form the t-loop structure. Telomeric proteins also protect telomeres from other DNA repair pathways and prevent the activation of the DNA damage signaling pathways (not shown). (C) The t-loop based primordial telomere. The proposed precursor to modern telomeres is a t-loop structure as depicted. The critical aspect of the t-loop is the strand-invasion (mediated by homologous recombination factors) of the telomere end into a repeated homologous sequence (gray box). The invaded repeat could either be close to the end or chromosome-internal. Any repetitive sequence of sufficient length to allow homologous recombination can fulfill this function. Although the strand-invasion would require a 3′ overhang, recruitment of a replisome and DNA synthesis would generate a structure lacking single-stranded DNA (shown on the left). The strand-invasion of the end blocks NHEJ and ssDNA recognition systems (e.g., SOS response), thus solving the end-protection problem. When the terminal sequences is extended by DNA replication, the end-replication problem is solved (right).

FIGURE 2

Group II introns and their role in chromosome linearization. (A) Steps involved in insertion of mobile Group II intron elements by target-primed reverse transcription. The Group II RNP recognizes the DNA target site and reverse splices into the top strand. The Group II endonuclease cleaves the bottom strand and the free 3′ OH is the primer for reverse-transcription. Host repair activities, which vary across organisms, complete the process (see Lambowitz and Belfort, 2015, for details on Group II introns). (B) Generation of a stable linear chromosome from a circular genome containing multiple Group II introns. A double strand break in one of the Group II introns can give rise to a linear chromosome that is stabilized by strand-invasion of the terminal Group II sequences into internal Group II introns. Such t-loop ends will be protected from ligation and allow extension of the terminal sequence (see Figure 1C). (C) Changes in Group II intron RT needed for telomerase function. Left: Reverse transcription of the Group II intron RNA that has been self-spliced (reverse reaction) into the genomic DNA. RT uses a 3′ end generated by endonucleolytic cleavage to prime reverse transcription of the covalently attached Group II intron RNA. Right: To function as a telomerase, the Group II RT has to be able to use the 3′ end of a chromosome to prime reverse transcription of a non-covalent RNA template bound to the enzyme.