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Review
. 2016 May 2;126(5):1621-9.
doi: 10.1172/JCI84547. Epub 2016 May 2.

The shelterin complex and hematopoiesis

Morgan Jones, Kamlesh Bisht, Sharon A Savage, Jayakrishnan Nandakumar, Catherine E Keegan, Ivan Maillard
Review

The shelterin complex and hematopoiesis

Morgan Jones et al. J Clin Invest. .

Abstract

Mammalian chromosomes terminate in stretches of repetitive telomeric DNA that act as buffers to avoid loss of essential genetic information during end-replication. A multiprotein complex known as shelterin prevents recognition of telomeric sequences as sites of DNA damage. Telomere erosion contributes to human diseases ranging from BM failure to premature aging syndromes and cancer. The role of shelterin telomere protection is less understood. Mutations in genes encoding the shelterin proteins TRF1-interacting nuclear factor 2 (TIN2) and adrenocortical dysplasia homolog (ACD) were identified in dyskeratosis congenita, a syndrome characterized by somatic stem cell dysfunction in multiple organs leading to BM failure and other pleiotropic manifestations. Here, we introduce the biochemical features and in vivo effects of individual shelterin proteins, discuss shelterin functions in hematopoiesis, and review emerging knowledge implicating the shelterin complex in hematological disorders.

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Figures

Figure 1
Figure 1. Organization and molecular functions of the shelterin complex at telomeric ends.
Telomeric DNA contains repetitive sequences forming a long double-stranded region (right) followed by a shorter G-rich, single-stranded overhang (left). The shelterin complex consists of six proteins (TRF1, TRF2, RAP1, TIN2, POT1, and TPP1) that bind the double-stranded and single-stranded regions of telomeric DNA. TPP1 is encoded by the gene ACD. Shelterin proteins play important, nonredundant roles in preventing activation of DDR pathways at chromosome ends, including ATR/CHK1 activation by exposed ssDNA and ATM/CHK2 activation by double-stranded DNA. Shelterin proteins prevent attempted repair by HR and NHEJ mechanisms. Additional pathways and crosstalk between pathways exist but are not represented here for the sake of simplicity.
Figure 2
Figure 2. Structure of TPP1 and TIN2 shelterin proteins, highlighting key mutations identified in patients with dyskeratosis congenita.
(A) TPP1 (encoded by ACD) contains an OB fold domain (OB), which recruits telomerase through an exposed TEL patch, as well as a POT1-binding domain and a TIN2-binding domain. Human variants identified in dyskeratosis congenita families are shown in red (K170Δ, P491T). Essential surface-exposed amino acids in the TEL patch are shown in yellow, while the mutation identified in dyskeratosis congenita is shown in red. Numbers indicate amino acid positions. (B) TIN2 (encoded by TINF2) contains an N-terminal TRF2-binding region, followed by TPP1-binding and TRF1-binding domains. Selected recurrent mutations identified in dyskeratosis congenita patients are indicated in red (K280E, R282H, P283S). Multiple other mutations affecting the 280–300 amino acid cluster were reported but are not depicted. Note that the hotspot for dyskeratosis congenita mutations lies outside of all known protein-binding regions of TIN2. Numbers indicate amino acid positions.
Figure 3
Figure 3. Schematic representation of human proteins affected by germline mutations in dyskeratosis congenita and related disorders.
Mutations affecting 11 different proteins have been reported to date in dyskeratosis congenita and related disorders, as indicated by colored structures. TERT, TERC, dyskerin, NHP2, NOP10, and TCAB1 are important for the processing, integrity, and/or function of the telomerase holoenzyme, a ribonucleoprotein complex containing TERC RNA and the catalytic TERT protein with reverse transcriptase activity. TIN2 and TPP1 (encoded by ACD) are members of the shelterin complex (see Figure 1). CTC1 belongs to a complex that regulates telomere C-strand synthesis and telomere replication. RTEL1 is important for telomere replication and stability. PARN was recently described to control processing of TERC RNA as well as mRNAs of other telomere maintenance genes.
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References

    1. Palm W, de Lange T. How shelterin protects mammalian telomeres. Annu Rev Genet. 2008;42:301–334. doi: 10.1146/annurev.genet.41.110306.130350. - DOI - PubMed
    1. Xin H, et al. TPP1 is a homologue of ciliate TEBP-β and interacts with POT1 to recruit telomerase. Nature. 2007;445(7127):559–562. doi: 10.1038/nature05469. - DOI - PubMed
    1. Abreu E, et al. TIN2-tethered TPP1 recruits human telomerase to telomeres in vivo. Mol Cell Biol. 2010;30(12):2971–2982. doi: 10.1128/MCB.00240-10. - DOI - PMC - PubMed
    1. Zhong FL, Batista LF, Freund A, Pech MF, Venteicher AS, Artandi SE. TPP1 OB-fold domain controls telomere maintenance by recruiting telomerase to chromosome ends. Cell. 2012;150(3):481–494. doi: 10.1016/j.cell.2012.07.012. - DOI - PMC - PubMed
    1. Nandakumar J, Bell CF, Weidenfeld I, Zaug AJ, Leinwand LA, Cech TR. The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity. Nature. 2012;492(7428):285–289. doi: 10.1038/nature11648. - DOI - PMC - PubMed

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