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Review
. 2022 Oct;28(10):882-891.
doi: 10.1016/j.molmed.2022.08.001. Epub 2022 Sep 1.

Telomere biology disorders: time for moving towards the clinic?

Luis F Z Batista  1 , Inderjeet Dokal  2 , Roy Parker  3
Affiliations
Review

Telomere biology disorders: time for moving towards the clinic?

Luis F Z Batista et al. Trends Mol Med. 2022 Oct.

Abstract

Telomere biology disorders (TBDs) are a group of rare diseases caused by mutations that impair telomere maintenance. Mutations that cause reduced levels of TERC/hTR, the telomerase RNA component, are found in most TBD patients and include loss-of-function mutations in hTR itself, in hTR-binding proteins [NOP10, NHP2, NAF1, ZCCHC8, and dyskerin (DKC1)], and in proteins required for hTR processing (PARN). These patients show diverse clinical presentations that most commonly include bone marrow failure (BMF)/aplastic anemia (AA), pulmonary fibrosis, and liver cirrhosis. There are no curative therapies for TBD patients. An understanding of hTR biogenesis, maturation, and degradation has identified pathways and pharmacological agents targeting the poly(A) polymerase PAPD5, which adds 3'-oligoadenosine tails to hTR to promote hTR degradation, and TGS1, which modifies the 5'-cap structure of hTR to enhance degradation, as possible therapeutic approaches. Critical next steps will be clinical trials to establish the effectiveness and potential side effects of these compounds in TBD patients.

Keywords: PAPD5; RNA processing; bone marrow failure; liver fibrosis,; pulmonary fibrosis; telomerase; telomere shortening.

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Conflict of interest statement

Declaration of interests R.P. is a founder and consultant for Faze Medicines. The other authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.. Shelterin and telomerase bind to telomeres.
(A) Depiction of the 6-subunit shelterin complex (left) and its association with telomeric DNA (right). Shelterin components TRF1 and TRF2 (depicted as dimers) bind to double-stranded telomere DNA. RAP1 binds directly to TRF2, while TIN2 binds to both TRF1 and TRF2. TPP1 binds to TIN2 and to POT1, which also binds to the single-stranded 3’ overhang. TPP1 also binds to TERT, and recruits telomerase to telomeres (not depicted in the figure). Formation of t-loop and d-loop structures are shown, which help repress activation of DNA damage responses at telomeres. (B) Depiction of hTR (black line) and its many binding partners, composing the telomerase complex. Different domains of hTR are highlighted. TERT binds to hTR through the CR4/5 and template/pseudoknot domains. The dyskerin complex binds to hTR through the H/ACA domain, which contains a single-strand hinge (H-box), followed by a loop and the ACA sequence. The H/ACA domain contains the CAB box region, where TCAB1 binds to. Finally, the template region of hTR also binds to the 3’ end of telomeres. In (A) and (B), shelterin and telomerase components are not depicted to scale or abundance.
Figure 2.
Figure 2.. hTR biogenesis and processing.
Nascent hTR contains 3’ extensions (depicted in blue) that are polyadenylated by PAPD5, leading to their exonucleolytic decay by the exosome. Alternatively, 3’ exonucleases can trims these 3’ extensions, leading to formation of mature hTR molecules. PAPD5 can also adenylate fully trimmed hTR molecules to promote their 3’ to 5’ degradation, which is increased in patient cells lacking dyskerin. Binding of hTR to the dyskerin complex (through its H/ACA domain) increases hTR stability. Binding to TCAB1 (through its CAB box domain) is necessary for telomerase trafficking to Cajal bodies (not shown), which aids in the formation of functional telomerase complexes.
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References

    1. Palm W and de Lange T, How shelterin protects mammalian telomeres. Annu Rev Genet, 2008. 42: p. 301–34. - PubMed
    1. Chan SR and Blackburn EH, Telomeres and telomerase. Philos Trans R Soc Lond B Biol Sci, 2004. 359(1441): p. 109–21. - PMC - PubMed
    1. Lim CJ and Cech TR, Shaping human telomeres: from shelterin and CST complexes to telomeric chromatin organization. Nat Rev Mol Cell Biol, 2021. 22(4): p. 283–298. - PMC - PubMed
    1. Lazzerini-Denchi E and Sfeir A, Stop pulling my strings - what telomeres taught us about the DNA damage response. Nat Rev Mol Cell Biol, 2016. 17(6): p. 364–78. - PMC - PubMed
    1. Glousker G and Lingner J, Challenging endings: How telomeres prevent fragility. Bioessays, 2021. 43(10): p. e2100157. - PubMed

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