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The shelterin complex and hematopoiesis
Morgan Jones, … , Catherine E. Keegan, Ivan Maillard
Morgan Jones, … , Catherine E. Keegan, Ivan Maillard
Published May 2, 2016
Citation Information: J Clin Invest. 2016;126(5):1621-1629. https://doi.org/10.1172/JCI84547.
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The shelterin complex and hematopoiesis

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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.

Authors

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

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Figure 1

Organization and molecular functions of the shelterin complex at telomeric ends.

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Organization and molecular functions of the shelterin complex at telomer...
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.
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