title: p53 mediates loss of hematopoietic stem cell function and lymphopenia in Mysm1 deficiency.
abstract: MYSM1 is a chromatin-binding transcriptional cofactor that deubiquitinates histone H2A. Studies of Mysm1-deficient mice have shown that it is essential for hematopoietic stem cell (HSC) function and lymphopoiesis. Human carriers of a rare MYSM1-inactivating mutation display similar lymphopoietic deficiencies. However, the mechanism by which MYSM1 regulates hematopoietic homeostasis remains unclear. Here, we show that Mysm1-deficiency results in p53 protein elevation in many hematopoietic cell types. p53 is a central regulator of cellular stress responses and HSC homeostasis. We thus generated double-knockout mice to assess a potential genetic interaction between Mysm1 and p53 in hematopoiesis. Mysm1(-/-)p53(-/-) mouse characterization showed a full rescue of Mysm1(-/-) developmental and hematopoietic defects. This included restoration of lymphopoiesis, and HSC numbers and functions. These results establish p53 activation as the driving mechanism for hematopoietic abnormalities in Mysm1 deficiency. Our findings may advance the understanding of p53 regulation in hematopoiesis and implicate MYSM1 as a potential p53 cofactor.
authors.affiliation: Department of Physiology, Complex Traits Group, and.
authors.forename: Jad I
authors.initials: JI
authors.lastname: Belle
authors.affiliation: Complex Traits Group, and Department of Biochemistry, McGill University, Montreal, QC, Canada;
authors.forename: David
authors.initials: D
authors.lastname: Langlais
authors.affiliation: Department of Physiology, Complex Traits Group, and.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Petrov
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom; and.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Pardo
authors.affiliation: Department of Physiology, The Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
authors.forename: Russell G
authors.initials: RG
authors.lastname: Jones
authors.affiliation: Complex Traits Group, and Department of Biochemistry, McGill University, Montreal, QC, Canada; The Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gros
authors.affiliation: Department of Physiology, Complex Traits Group, and.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Nijnik
mesh_terms: D000818:Animals; D010450:Endopeptidases / Q000235:genetics*; D017353:Gene Deletion; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D008231:Lymphopenia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D038041:Lymphopoiesis; D051379:Mice; D018345:Mice, Knockout; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases
chemical_list: D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D010450:Endopeptidases; C570173:MYSM1 protein, mouse; D064570:Ubiquitin-Specific Proteases