Proteomics and functional analysis of hematopoietic progenitor cells in hypomorphic Dkc1 mutant mice

• Grant number: 12/17588-8
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: January 01, 2013
• End date: December 31, 2014
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Eduardo Magalhães Rego
• Grantee: Antonio Roberto Lucena de Araújo
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Dyskeratosis Congenita (DC) is a rare inherited syndrome characterized by mucocutaneous manifestations, bone marrow (BM) failure and increased susceptibility to cancer. X-linked DC (DC-X) is the most severe form of the syndrome and is caused by mutations in the DKC1 gene that encodes dyskerin, a putative pseudouridine synthase which mediate the posttranscriptional modification of ribosomal RNA (rRNA) through the conversion of uridine (U) to pseudouridine (¨). Recent studies have shown that defects in pseudouridylation of ribosomal RNA can compromise the IRES-dependent translation of specific mRNA, leading to unbalanced expression of proteins responsible for distinct cellular processes, such as apoptosis, cell quiescence and differentiation. Ruggero et al. have demonstrated that hypomorphic Dkc1m mice Pancytopenia associated with hypocellularity of the bone marrow and increased susceptibility to cancer. However, the cellular and molecular mechanisms leading to BM failure in X-DC remain unknown. Using stable isotope labelling of amino acids (SILAC) in vivo and competitive transplantation assays of hematopoietic progenitors, the present study aims to identify proteins associated with BM failure and whose expression/function are altered as a result of down regulation of dyskerin.