title: RPL27A is a target of miR-595 and may contribute to the myelodysplastic phenotype through ribosomal dysgenesis.
abstract: We investigated the functional consequences following deletion of a microRNA (miR) termed miR-595 which resides on chromosome 7q and is localised within one of the commonly deleted regions identified for Myelodysplasia (MDS) with monosomy 7 (-7)/isolated loss of 7q (7q-). We identified several targets for miR-595, including a large ribosomal subunit protein RPL27A. RPL27A downregulation induced p53 activation, apoptosis and inhibited proliferation. Moreover, p53-independent effects were additionally identified secondary to a reduction in the ribosome subunit 60s. We confirmed that RPL27A plays a pivotal role in the maintenance of nucleolar integrity and ribosomal synthesis/maturation. Of note, RPL27A overexpression, despite showing no significant effects on p53 mRNA levels, did in fact enhance cellular proliferation. In normal CD34+ cells, RPL27A knockdown preferentially blocked erythroid proliferation and differentiation. Lastly, we show that miR-595 expression appears significantly downregulated in the majority of primary samples derived from MDS patients with (-7)/(7q-), in association with RPL27A upregulation. This significant downregulation of miR-595 is also apparent when higher risk MDS cases are compared to lower risk cases. The potential clinical importance of these findings requires further validation.
authors.affiliation: Department of Haematological Medicine, King's College London School of Medicine, London, UK.|Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah, Saudi Arabia.
authors.forename: Heba A
authors.initials: HA
authors.lastname: Alkhatabi
authors.affiliation: Department of Haematological Medicine, King's College London School of Medicine, London, UK.|Department of Hematology, King's College Hospital, London, UK.
authors.forename: Donal P
authors.initials: DP
authors.lastname: McLornan
authors.affiliation: Department of Haematological Medicine, King's College London School of Medicine, London, UK.|Department of Hematology, King's College Hospital, London, UK.
authors.forename: Austin G
authors.initials: AG
authors.lastname: Kulasekararaj
authors.affiliation: Department of Haematological Medicine, King's College London School of Medicine, London, UK.
authors.forename: Farooq
authors.initials: F
authors.lastname: Malik
authors.affiliation: Department of Haematological Medicine, King's College London School of Medicine, London, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seidl
authors.affiliation: Department of Haematological Medicine, King's College London School of Medicine, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Darling
authors.affiliation: Department of Haematological Medicine, King's College London School of Medicine, London, UK.
authors.forename: Joop
authors.initials: J
authors.lastname: Gaken
authors.affiliation: Department of Haematological Medicine, King's College London School of Medicine, London, UK.|Department of Hematology, King's College Hospital, London, UK.
authors.forename: Ghulam J
authors.initials: GJ
authors.lastname: Mufti
mesh_terms: D049109:Cell Proliferation / Q000502:physiology; D015331:Cohort Studies; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D020014:K562 Cells; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism*; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014162:Transfection; D020298:U937 Cells
chemical_list: D035683:MicroRNAs; C486160:RPL27A protein, human; D012269:Ribosomal Proteins; C000609695:microRNA595 microRNA, human
keywords: chromosome; haemopoiesis; microRNA; myelodysplasia; ribosome