Subtelomeric Transcription and its Regulation

Abstract

The subtelomeres, highly heterogeneous repeated sequences neighboring telomeres, are transcribed into coding and noncoding RNAs in a variety of organisms. Telomereproximal subtelomeric regions produce non-coding transcripts i.e., ARRET, αARRET, subTERRA, and TERRA, which function in telomere maintenance. The role and molecular mechanisms of the majority of subtelomeric transcripts remain unknown. This review depicts the current knowledge and puts into perspective the results obtained in different models from yeasts to humans.

Keywords: noncoding RNA; repeated sequences; subtelomeres; transcription.

Graphical abstract

Fig. 1

Overview of telomeric structures and potential molecular mechanisms of action of telomeric and subtelomeric transcripts. Schematic representation of a chromosome highlighting the telomeres (rainbow squares) at its extremities. Telomeres (in yellow) are composed of tandem repeats bound by shelterin complex and telomerase, which elongates telomeric DNA. TPE intensity decreases toward the centromere. a. Schematic representation of a telomeric t-loop, including a displacement loop (D-loop). b. G-quadruplexes formed on a telomeric 3′G-overhang. c. Telomeric R-loop (TRL) constituted by RNAPII-transcribed TERRA and telomeric sequences. Additionally, G-quadruplexes can be formed by a single G-rich strand. d. Schematic DNA loop representing TPE-OLD and other telomere long-range interactions.

Fig. 2

Organization of subtelomeric regions in various organisms. In general subtelomeres are composed of two regions: a telomere-proximal region also called TAS (for Telomere-Associated Sequences; in green) and a telomere-distal region (in red). Telomeric repeats are represented as a black arrow. In yeast S. cerevisiae, TAS can be found in two flavors: TAS containing Y′ elements or not (X-only subtelomeres). The X-core element contains ARS (ACS) sequences binding the Abf1 protein and STR repeats with Tbf1 protein-binding sites. The telomere-distal region encloses subtelomeric genes families. ITS (Interspersed/Interstitial/Internal Telomeric Repeats; in yellow) are more or less degenerated telomeric repeats present in TAS between X and Y′ elements. In S. pombe, TAS are called SH regions and contain cenH (centromere-homologous sequence) and telomere-linked helicases (tlh) encoded at chromosomes I (tlh1+) and II (tlh2+). These putative helicases are members of the recQ family and show sequence homology with the dh and dg repeats found at centromeres [186]. The Sgo domain, shown in violet, represents a Sgo2-binding barrier, which controls the spreading of subtelomeric heterochromatin between proximal and distal regions. The telomere-distal region called “knob” contains chromosome-specific sequences and the nucleosome free region (NF) at its centromere-proximal end. In P. falciparum, six telomere-associated repeat elements (TARE1-6/Rap20) and several 12-base SPE sites (binding SPE2 interacting protein 2, PfSIP2) are located between var genes and TAS. 60 var genes are positioned in telomere-distal regions within subtelomeres; rif and ste genes are frequently found in their vicinity [187]. In G. domesticus, tandem repeats PO41, CNM, EcoRI/XhoI and PIR compose TAS. In H. sapiens, Subtelomeric Repeats (SRE/Srpt) comprise about 25% of the most distal 500 kb and 80% of the most distal 100 kb of the chromosome ends [50]. ITS repeats are found between different genetic elements. The TAR1 element, immediately adjacent to the telomeric repeats, is a variably sized (0–2 kb) sequence segment bearing similarity to the TAR1 repeat family.

Fig. 3

lncRNA expressed at subtelomeric regions. The telomere-proximal region is shown in green and the telomere-distal region in red. In various species, TERRA (G-rich) is transcribed from subtelomere-embedded promoters through telomeric repeats (black arrow) and contains subtelomeric sequences at its 5’. Telomeric repeats produce also ARIA (C-rich) transcripts composed exclusively of telomeric sequences. lncRNA species encoded within TAS regions are depicted in green. Upper transcripts are transcribed toward the telomere (subTERRA-XUT in S. cerevisiae (S.c), αARRET in S. pombe (S.p), PO41 in G. domesticus (G.d), subtelomeric transcripts in L. infantum (L.i) and lncRNA-TARE in P. falciparum (P.f)). lncRNAs transcribed toward the centromere (subTERRA-CUT in S. cerevisiae, ARRET in S. pombe, PO41 in G. domesticus, subtelomeric transcripts in L. infantum) are represented below. In P. falciparum different var transcripts are produced from var genes (pink rectangle); var coding full-length transcript (red line), and var sterile noncoding transcripts (dashed red lines) transcribed in both direction from the intron. TAS and telomere-distal regions harbor specific chromatin states represented here as arrays of violet and blue nucleosomes. Decreasing TPE direction is shown. H.s stands for Homo sapiens, M.m for Mus musculus.