Page 59 - Haematologica - Vol. 105 n. 6 - June 2020

Hematopoiesis
DKC1 is a transcriptional target of GATA1 and drives upregulation of telomerase activity in normal human erythroblasts
Laura A. Richards,1* Ashu Kumari,1* Kathy Knezevic,2 Julie AI Thoms,2,3 Georg von Jonquieres,1 Christine E. Napier,1 Zara Ali,4 Rosemary O’Brien,1 Jonathon Marks-Bluth,2 Michelle F. Maritz,1 Hilda A Pickett,5 Jonathan Morris,6 John E. Pimanda2,3 and Karen L. MacKenzie1,4,7,8
1Children’s Cancer Institute Australia, Randwick; 2Adult Cancer Program, Prince of Wales Clinical School, Lowy Cancer Research Centre, UNSW, Sydney; 3School of Medical Sciences, UNSW, Sydney; 4Cancer Research Unit, Children’s Medical Research Institute, Westmead; 5Telomere Length Regulation Unit, Children’s Medical Research Institute, Westmead; 6The University of Sydney School of Medicine, Kolling Institute of Medical Research, St Leonards; 7School of Women’s and Children’s Health, UNSW, Sydney and 8Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
*LAR and AK contributed equally as co-first authors
ABSTRACT
Telomerase is a ribonucleoprotein complex that maintains the length and integrity of telomeres, and thereby enables cellular proliferation. Understanding the regulation of telomerase in hematopoietic cells is relevant to the pathogenesis of leukemia, in which telomerase is constitu- tively activated, as well as bone marrow failure syndromes that feature telomerase insufficiency. Past studies showing high levels of telomerase in human erythroblasts and a prevalence of anemia in disorders of telomerase insufficiency provide the rationale for investigating telomerase regulation in erythroid cells. Here it is shown for the first time that the telomerase RNA- binding protein dyskerin (encoded by DKC1) is dramatically upregulated as human hematopoietic stem and progenitor cells commit to the erythroid lineage, driving an increase in telomerase activity in the presence of limiting amounts of TERT mRNA. It is also shown that upregulation of DKC1 was necessary for expansion of glycophorin A+ erythroblasts and sufficient to extend telomeres in erythroleukemia cells. Chromatin immunoprecipita- tion and reporter assays implicated GATA1-mediated transcriptional regu- lation of DKC1 in the modulation of telomerase in erythroid lineage cells. Together these results describe a novel mechanism of telomerase regulation in erythroid cells which contrasts with mechanisms centered on transcrip- tional regulation of TERT that are known to operate in other cell types. This is the first study to reveal a biological context in which telomerase is upreg- ulated by DKC1 and to implicate GATA1 in telomerase regulation. The results from this study are relevant to hematopoietic disorders involving DKC1 mutations, GATA1 deregulation and/or telomerase insufficiency.
Introduction
Telomerase is a ribonucleoprotein complex that maintains the length and integri- ty of chromosomal-end structures called telomeres and thereby enables continuous cellular proliferation.1 The minimum essential components of the human telom- erase holoenzyme are a specialized reverse transcriptase (TERT) and a non-coding RNA (TERC) that includes an RNA template domain for priming synthesis of telomeric repeats. Active human telomerase ribonuclear proteins also include the RNA binding and modifying protein, dyskerin. Dyskerin, encoded by DKC1, aug- ments telomerase activity by directly binding to TERC to confer the structural rigidity and stability necessary for its accumulation and function.2,3
Telomerase enzyme activity underpins the unrestricted proliferation of cancer cells in approximately 80-90% of malignancies, including acute leukemias and lym-
Ferrata Storti Foundation
Haematologica 2020 Volume 105(6):1517-1526
Correspondence:
KAREN L MACKENZIE
kmackenzie@cmri.org.au
Received: January 4, 2019. Accepted: August 13, 2019. Pre-published: August 14, 2019.
doi:10.3324/haematol.2018.215699
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/6/1517
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