Mechanisms of the Evolutionary Chromosome Plasticity: Integrating the ‘Centromere-from-Telomere' Hypothesis with Telomere Length Regulation

The ‘centromere-from-telomere' hypothesis proposed by Villasante et al. [2007a] aims to explain the evolutionary origin of the eukaryotic chromosome. The hypothesis is based on the notion that the process of eukaryogenesis was initiated by adaptive responses of the symbiont eubacterium and its archaeal host to their new conditions. The adaptive responses included fragmentation of the circular genome of the host into multiple linear fragments with free DNA ends. The action of mobile genetic elements stabilized the free DNA ends resulting in the formation of proto-telomeres. Sequences next to the proto-telomeres, the subtelomeric sequences, were immediately targeted as the new cargo by the tubulin-based cytoskeleton, thus becoming proto-centromeres. A period of genomic instability followed. Eventually, functioning centromeres and telomeres emerged heralding the arrival of the eukaryotic chromosome in the evolution. This paper expands the ‘centromere-from-telomere' hypothesis by integrating it with 2 sets of data: chromosome-specific telomere length distribution and chromomere size gradient. The integration adds a new dimension to the hypothesis but also provides an insight into the mechanisms of chromosome plasticity underlying karyotype evolution.

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The Ku Heterodimer Performs Separable Activities at Double-Strand Breaks and Chromosome Termini

Molecular and Cellular Biology ◽

10.1128/mcb.23.22.8202-8215.2003 ◽

2003 ◽

Vol 23 (22) ◽

pp. 8202-8215 ◽

Cited By ~ 68

Author(s):

Alison A. Bertuch ◽

Victoria Lundblad

Keyword(s):

Telomere Length ◽

Large Subunit ◽

Double Strand Breaks ◽

Detailed Characterization ◽

Strand Breaks ◽

Functional Differences ◽

Length Regulation ◽

Telomere Length Regulation ◽

Dna Ends

ABSTRACT The Ku heterodimer functions at two kinds of DNA ends: telomeres and double-strand breaks. The role that Ku plays at these two classes of termini must be distinct, because Ku is required for accurate and efficient joining of double-strand breaks while similar DNA repair events are normally prohibited at chromosome ends. Toward defining these functional differences, we have identified eight mutations in the large subunit of the Saccharomyces cerevisiae Ku heterodimer (YKU80) which retain the ability to repair double-strand breaks but are severely impaired for chromosome end protection. Detailed characterization of these mutations, referred to as yku80tel alleles, has revealed that Ku performs functionally distinct activities at subtelomeric chromatin versus the end of the chromosome, and these activities are separable from Ku's role in telomere length regulation. While at the chromosome terminus, we propose that Ku participates in two different activities: it facilitates telomerase-mediated G-strand synthesis, thereby contributing to telomere length regulation, and it separately protects against resection of the C-strand, thereby contributing to protection of chromosome termini. Furthermore, we propose that the Ku heterodimer performs discrete sets of functions at chromosome termini and at duplex subtelomeric chromatin, via separate interactions with these two locations. Based on homology modeling with the human Ku structure, five of the yku80tel alleles mutate residues that are conserved between the yeast and human Ku80 proteins, suggesting that these mutations probe activities that are shared between yeast and humans.

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Rif1 regulates telomere length through conserved HEAT repeats

Nucleic Acids Research ◽

10.1093/nar/gkab206 ◽

2021 ◽

Vol 49 (7) ◽

pp. 3967-3980

Author(s):

Calla B Shubin ◽

Rini Mayangsari ◽

Ariel D Swett ◽

Carol W Greider

Keyword(s):

Dna Binding ◽

Telomere Length ◽

Functional Role ◽

Conserved Residues ◽

Binding Interface ◽

Binding Function ◽

Length Regulation ◽

Telomere Length Regulation ◽

Telomere Regulation ◽

Conserved Amino Acids

AbstractIn budding yeast, Rif1 negatively regulates telomere length, but the mechanism of this regulation has remained elusive. Previous work identified several functional domains of Rif1, but none of these has been shown to mediate telomere length. To define Rif1 domains responsible for telomere regulation, we localized truncations of Rif1 to a single specific telomere and measured telomere length of that telomere compared to bulk telomeres. We found that a domain in the N-terminus containing HEAT repeats, Rif1177–996, was sufficient for length regulation when tethered to the telomere. Charged residues in this region were previously proposed to mediate DNA binding. We found that mutation of these residues disrupted telomere length regulation even when Rif1 was tethered to the telomere. Mutation of other conserved residues in this region, which were not predicted to interact with DNA, also disrupted telomere length maintenance, while mutation of conserved residues distal to this region did not. Our data suggest that conserved amino acids in the region from 436 to 577 play a functional role in telomere length regulation, which is separate from their proposed DNA binding function. We propose that the Rif1 HEAT repeats region represents a protein-protein binding interface that mediates telomere length regulation.

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Cdc13 N-Terminal Dimerization, DNA Binding, and Telomere Length Regulation

Molecular and Cellular Biology ◽

10.1128/mcb.00515-10 ◽

2010 ◽

Vol 30 (22) ◽

pp. 5325-5334 ◽

Cited By ~ 23

Author(s):

Meghan T. Mitchell ◽

Jasmine S. Smith ◽

Mark Mason ◽

Sandy Harper ◽

David W. Speicher ◽

...

Keyword(s):

Dna Binding ◽

Telomere Length ◽

Functional Characterization ◽

Point Mutations ◽

Telomeric Dna ◽

Dna Binding Domains ◽

Binding Domains ◽

Length Regulation ◽

Telomere Length Regulation

ABSTRACT The essential yeast protein Cdc13 facilitates chromosome end replication by recruiting telomerase to telomeres, and together with its interacting partners Stn1 and Ten1, it protects chromosome ends from nucleolytic attack, thus contributing to genome integrity. Although Cdc13 has been studied extensively, the precise role of its N-terminal domain (Cdc13N) in telomere length regulation remains unclear. Here we present a structural, biochemical, and functional characterization of Cdc13N. The structure reveals that this domain comprises an oligonucleotide/oligosaccharide binding (OB) fold and is involved in Cdc13 dimerization. Biochemical data show that Cdc13N weakly binds long, single-stranded, telomeric DNA in a fashion that is directly dependent on domain oligomerization. When introduced into full-length Cdc13 in vivo, point mutations that prevented Cdc13N dimerization or DNA binding caused telomere shortening or lengthening, respectively. The multiple DNA binding domains and dimeric nature of Cdc13 offer unique insights into how it coordinates the recruitment and regulation of telomerase access to the telomeres.

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Regulating telomere length from the inside out: The replication fork model

10.1101/041772 ◽

2016 ◽

Author(s):

Carol W Greider

Keyword(s):

Telomere Length ◽

Alternative Model ◽

Replication Fork ◽

Molecular Level ◽

Origin Firing ◽

Length Regulation ◽

Telomere Length Regulation ◽

Inside Out ◽

Counting Model

Telomere length is regulated around an equilibrium set point. Telomeres shorten during replication and are lengthened by telomerase. Disruption of the length equilibrium leads to disease, thus it is important to understand the mechanisms that regulate length at the molecular level. The prevailing protein counting model for regulating telomerase access to elongate the telomere does not explain accumulating evidence of a role of DNA replication in telomere length regulation. Here I present an alternative model: the replication fork model that can explain how passage of a replication fork and regulation of origin firing affect telomere length.

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