{"id":{"repo_id":"unsw","oai_identifier":"oai:unsworks.library.unsw.edu.au:1959.4/58765"},"canonical_url":"https://search.dev.ndltd.org/etd/unsw/oai:unsworks.library.unsw.edu.au:1959.4/58765","repository":{"repo_id":"unsw","name":"University of New South Wales","base_url":"https://unsworks.unsw.edu.au/oai/provider"},"display":{"title":"Suppression of telomerase component dyskerin in human haematopoietic progenitor cells","abstract":"Telomerase is a multi-component enzyme functioning to maintain chromosomal-end structures, called telomeres. Telomerase insufficiency, due to mutations in telomerase associated genes including dyskerin (encoded by DKC1) and TERC, is a hallmark of a subgroup of inherited and acquired haematopoietic disorders, such as dyskeratosis congenita (DC) and aplastic anaemia (AA) which currently lack effective pharmacologic treatment. Replicative deficiency of human haematopoietic progenitor cells (HPCs) has been attributed to inadequate telomere length reserve. However, the unexplained phenotypic heterogeneity of these disorders suggest there may be additional mechanisms involved. Dyskerin is a nucleolar protein that stabilises the RNA template component of telomerase, TERC and other small non-coding RNAs of biological importance. It is currently unclear whether the telomerase independent functions of dyskerin have an additional contribution to the pathogenesis of diseases of telomerase insufficiency. The objective of this study was to delineate the effects of dyskerin depletion on HPC function, with comparison to TERC suppression to distinguish telomerase dependent and independent effects. Inducible shRNA knockdown lentiviral vectors targeting either DKC1 or TERC were constructed for transduction into human HPCs. Using this model, it was confirmed that depletion of either dyskerin or TERC effectively suppressed telomerase activity and reduced the proliferative capacity of HPCs without affecting differentiation, however a more dramatic proliferative effect was observed with suppression of dyskerin compared with TERC. RNA sequencing analysis revealed non-coding RNAs comprised 40% of all genes differentially regulated by DKC1 suppression. Of these, 65% were H/ACA motif containing RNAs, consistent with the roles of dyskerin as a H/ACA small non-coding RNA binding ribonucleoprotein. Further telomerase independent effects for dyskerin was confirmed with enrichment of gene pathways involved in the G1/S cell cycle arrest, MYC signalling, and an enrichment of miR-30 target genes. This study therefore provides evidence of molecular alterations beyond a telomerase defect, that may contribute to haematopoietic dysfunction in disorders characterised by mutations in DKC1.","abstract_html":"Telomerase is a multi-component enzyme functioning to maintain chromosomal-end structures, called telomeres. Telomerase insufficiency, due to mutations in telomerase associated genes including dyskerin (encoded by DKC1) and TERC, is a hallmark of a subgroup of inherited and acquired haematopoietic disorders, such as dyskeratosis congenita (DC) and aplastic anaemia (AA) which currently lack effective pharmacologic treatment. Replicative deficiency of human haematopoietic progenitor cells (HPCs) has been attributed to inadequate telomere length reserve. However, the unexplained phenotypic heterogeneity of these disorders suggest there may be additional mechanisms involved. Dyskerin is a nucleolar protein that stabilises the RNA template component of telomerase, TERC and other small non-coding RNAs of biological importance. It is currently unclear whether the telomerase independent functions of dyskerin have an additional contribution to the pathogenesis of diseases of telomerase insufficiency. The objective of this study was to delineate the effects of dyskerin depletion on HPC function, with comparison to TERC suppression to distinguish telomerase dependent and independent effects. Inducible shRNA knockdown lentiviral vectors targeting either DKC1 or TERC were constructed for transduction into human HPCs. Using this model, it was confirmed that depletion of either dyskerin or TERC effectively suppressed telomerase activity and reduced the proliferative capacity of HPCs without affecting differentiation, however a more dramatic proliferative effect was observed with suppression of dyskerin compared with TERC. RNA sequencing analysis revealed non-coding RNAs comprised 40% of all genes differentially regulated by DKC1 suppression. Of these, 65% were H/ACA motif containing RNAs, consistent with the roles of dyskerin as a H/ACA small non-coding RNA binding ribonucleoprotein. Further telomerase independent effects for dyskerin was confirmed with enrichment of gene pathways involved in the G1/S cell cycle arrest, MYC signalling, and an enrichment of miR-30 target genes. This study therefore provides evidence of molecular alterations beyond a telomerase defect, that may contribute to haematopoietic dysfunction in disorders characterised by mutations in DKC1.","abstract_has_math":false,"creators":["Ali, Zara"],"institution":"UNSW, Sydney","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2017,"date_issued":"2017","date_published":"2017","updated_at":"2026-07-24T05:33:31Z","subjects":[],"languages":["EN"],"rights":["open access","CC BY-NC-ND 3.0","free_to_read"],"rights_urls":["https://purl.org/coar/access_right/c_abf2","https://creativecommons.org/licenses/by-nc-nd/3.0/au/"],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["https://doi.org/10.26190/unsworks/19992"],"render_values":[{"text":"https://doi.org/10.26190/unsworks/19992","href":"https://doi.org/10.26190/unsworks/19992","code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/1959.4/58765","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Ali, Zara"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2017"]},{"key":"dc:publisher","label":"Institution","values":["UNSW, Sydney"]},{"key":"dc:type","label":"Dc Type","values":["doctoral thesis","http://purl.org/coar/resource_type/c_db06"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["EN"]},{"key":"dc:rights","label":"Dc Rights","values":["open access","https://purl.org/coar/access_right/c_abf2","CC BY-NC-ND 3.0","https://creativecommons.org/licenses/by-nc-nd/3.0/au/","free_to_read"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/1959.4/58765","https://unsworks.unsw.edu.au/bitstreams/e5f2916d-0054-4f1b-8d96-4dc5f7543732/download","https://doi.org/10.26190/unsworks/19992"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Telomerase is a multi-component enzyme functioning to maintain chromosomal-end structures, called telomeres. Telomerase insufficiency, due to mutations in telomerase associated genes including dyskerin (encoded by DKC1) and TERC, is a hallmark of a subgroup of inherited and acquired haematopoietic disorders, such as dyskeratosis congenita (DC) and aplastic anaemia (AA) which currently lack effective pharmacologic treatment. Replicative deficiency of human haematopoietic progenitor cells (HPCs) has been attributed to inadequate telomere length reserve. However, the unexplained phenotypic heterogeneity of these disorders suggest there may be additional mechanisms involved. Dyskerin is a nucleolar protein that stabilises the RNA template component of telomerase, TERC and other small non-coding RNAs of biological importance. It is currently unclear whether the telomerase independent functions of dyskerin have an additional contribution to the pathogenesis of diseases of telomerase insufficiency. The objective of this study was to delineate the effects of dyskerin depletion on HPC function, with comparison to TERC suppression to distinguish telomerase dependent and independent effects. Inducible shRNA knockdown lentiviral vectors targeting either DKC1 or TERC were constructed for transduction into human HPCs. Using this model, it was confirmed that depletion of either dyskerin or TERC effectively suppressed telomerase activity and reduced the proliferative capacity of HPCs without affecting differentiation, however a more dramatic proliferative effect was observed with suppression of dyskerin compared with TERC. RNA sequencing analysis revealed non-coding RNAs comprised 40% of all genes differentially regulated by DKC1 suppression. Of these, 65% were H/ACA motif containing RNAs, consistent with the roles of dyskerin as a H/ACA small non-coding RNA binding ribonucleoprotein. Further telomerase independent effects for dyskerin was confirmed with enrichment of gene pathways involved in the G1/S cell cycle arrest, MYC signalling, and an enrichment of miR-30 target genes. This study therefore provides evidence of molecular alterations beyond a telomerase defect, that may contribute to haematopoietic dysfunction in disorders characterised by mutations in DKC1."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Suppression of telomerase component dyskerin in human haematopoietic progenitor cells"]}]}],"canonical_facts":{"dc:creator":["Ali, Zara"],"dc:date":["2017"],"dc:description":["Telomerase is a multi-component enzyme functioning to maintain chromosomal-end structures, called telomeres. Telomerase insufficiency, due to mutations in telomerase associated genes including dyskerin (encoded by DKC1) and TERC, is a hallmark of a subgroup of inherited and acquired haematopoietic disorders, such as dyskeratosis congenita (DC) and aplastic anaemia (AA) which currently lack effective pharmacologic treatment. Replicative deficiency of human haematopoietic progenitor cells (HPCs) has been attributed to inadequate telomere length reserve. However, the unexplained phenotypic heterogeneity of these disorders suggest there may be additional mechanisms involved. Dyskerin is a nucleolar protein that stabilises the RNA template component of telomerase, TERC and other small non-coding RNAs of biological importance. It is currently unclear whether the telomerase independent functions of dyskerin have an additional contribution to the pathogenesis of diseases of telomerase insufficiency. The objective of this study was to delineate the effects of dyskerin depletion on HPC function, with comparison to TERC suppression to distinguish telomerase dependent and independent effects. Inducible shRNA knockdown lentiviral vectors targeting either DKC1 or TERC were constructed for transduction into human HPCs. Using this model, it was confirmed that depletion of either dyskerin or TERC effectively suppressed telomerase activity and reduced the proliferative capacity of HPCs without affecting differentiation, however a more dramatic proliferative effect was observed with suppression of dyskerin compared with TERC. RNA sequencing analysis revealed non-coding RNAs comprised 40% of all genes differentially regulated by DKC1 suppression. Of these, 65% were H/ACA motif containing RNAs, consistent with the roles of dyskerin as a H/ACA small non-coding RNA binding ribonucleoprotein. Further telomerase independent effects for dyskerin was confirmed with enrichment of gene pathways involved in the G1/S cell cycle arrest, MYC signalling, and an enrichment of miR-30 target genes. This study therefore provides evidence of molecular alterations beyond a telomerase defect, that may contribute to haematopoietic dysfunction in disorders characterised by mutations in DKC1."],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/1959.4/58765","https://unsworks.unsw.edu.au/bitstreams/e5f2916d-0054-4f1b-8d96-4dc5f7543732/download","https://doi.org/10.26190/unsworks/19992"],"dc:language":["EN"],"dc:publisher":["UNSW, Sydney"],"dc:rights":["open access","https://purl.org/coar/access_right/c_abf2","CC BY-NC-ND 3.0","https://creativecommons.org/licenses/by-nc-nd/3.0/au/","free_to_read"],"dc:title":["Suppression of telomerase component dyskerin in human haematopoietic progenitor cells"],"dc:type":["doctoral thesis","http://purl.org/coar/resource_type/c_db06"]},"updated_at":"2026-07-24T05:33:31Z"}