Shelterin and subtelomeric DNA sequences control nucleosome maintenance and genome stability

Abstract

Telomeres and the shelterin complex cap and protect the ends of chromosomes. Telomeres are flanked by the subtelomeric sequences that have also been implicated in telomere regulation, although their role is not well defined. Here we show that, in Schizosaccharomyces pombe, the telomere-associated sequences (TAS) present on most subtelomeres are hyper-recombinogenic, have metastable nucleosomes, and unusual low levels of H3K9 methylation. Ccq1, a subunit of shelterin, protects TAS from nucleosome loss by recruiting the heterochromatic repressor complexes CLRC and SHREC, thereby linking nucleosome stability to gene silencing. Nucleosome instability at TAS is independent of telomeric repeats and can be transmitted to an intrachromosomal locus containing an ectopic TAS fragment, indicating that this is an intrinsic property of the underlying DNA sequence. When telomerase recruitment is compromised in cells lacking Ccq1, DNA sequences present in the TAS promote recombination between chromosomal ends, independent of nucleosome abundance, implying an active function of these sequences in telomere maintenance.We propose that Ccq1 and fragile subtelomeres co-evolved to regulate telomere plasticity by controlling nucleosome occupancy and genome stability.

Spreading and epigenetic inheritance of heterochromatin require a critical density of histone H3 lysine 9 tri-methylation

“…Shelterin forms a complex with ClrC and is involved in heterochromatin assembly at telomeres and other loci (47)(48)(49)(50). When Shelterin-mediated heterochromatin assembly is compromised, silencing factors are released and redistributed to other heterochromatic loci (51).…”

Telomere-driven mutational processes in yeast

“…1d) contributes to nucleosome deposition at subtelomeres; ccq1 mutant cells show further depletion of nucleosomes at telomeres compared to wildtype cells, and subsequently display a hyper-recombinogenic phenotype among subtelomeric homologous sequences. Therefore, in both yeasts histone density at chromosome extremities is key to regulating telomere fate [31].…”

Subtelomeric Chromatin in the Fission Yeast S. pombe

“…Ccq1 associates with Tpz1 and is responsible for recruiting telomerase to maintain telomere repeat length [ 66 , 67 , 68 , 69 , 70 , 71 ]. Ccq1 also physically interacts with and recruits ClrC and SHREC to telomeric DNA repeats [ 52 , 72 , 73 , 74 , 75 ] (see Figure 2 ). Dissection of the interplay between Ccq1 and its binding partners the telomerase component Est1 and Clr3-SHREC suggests that Ccq1 interaction with these components is mutually exclusive and results in both positive and negative regulation of telomere length [ 71 ].…”

“…In contrast to other heterochromatic loci, the assembly of heterochromatin on TAS domains occurs independent of RNAi. TAS domains were recently shown to have very low nucleosome occupancy, with only about one third of the occupancy seen in euchromatic regions [ 74 ]. This at first seems counter-intuitive since repressed regions normally are enriched for repressive histone marks such as H3K9me2/3, and low nucleosome occupancy is refractory to heterochromatin spreading [ 54 , 55 ].…”

“…It is possible, however, that the low nucleosome density promotes access of repressive factors that suppress transcription within these domains (such as Ccq1). The low nucleosome occupancy is an intrinsic feature of the TAS sequence and is not linked to proximity to telomeric repeats since insertion of a partial TAS sequence into an euchromatic environment yielded the same nucleosome-depletion at the ectopic site [ 74 ]. This loss of nucleosomes is likely due to the AT-rich sequence at TAS sequences, which precludes nucleosome positioning [ 54 , 76 ].…”