title: Inactivation of chk2 and mus81 leads to impaired lymphocytes development, reduced genomic instability, and suppression of cancer.
abstract: Chk2 is an effector kinase important for the activation of cell cycle checkpoints, p53, and apoptosis in response to DNA damage. Mus81 is required for the restart of stalled replication forks and for genomic integrity. Mus81(Δex3-4/Δex3-4) mice have increased cancer susceptibility that is exacerbated by p53 inactivation. In this study, we demonstrate that Chk2 inactivation impairs the development of Mus81(Δex3-4/Δex3-4) lymphoid cells in a cell-autonomous manner. Importantly, in contrast to its predicted tumor suppressor function, loss of Chk2 promotes mitotic catastrophe and cell death, and it results in suppressed oncogenic transformation and tumor development in Mus81(Δex3-4/Δex3-4) background. Thus, our data indicate that an important role for Chk2 is maintaining lymphocyte development and that dual inactivation of Chk2 and Mus81 remarkably inhibits cancer.
authors.affiliation: Ontario Cancer Institute, University Health Network and Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors.forename: Samah
authors.initials: S
authors.lastname: El Ghamrasni
authors.forename: Ashwin
authors.initials: A
authors.lastname: Pamidi
authors.forename: Marie Jo
authors.initials: MJ
authors.lastname: Halaby
authors.forename: Miyuki
authors.initials: M
authors.lastname: Bohgaki
authors.forename: Renato
authors.initials: R
authors.lastname: Cardoso
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Shriram
authors.initials: S
authors.lastname: Venkatesan
authors.forename: Swaminathan
authors.initials: S
authors.lastname: Sethu
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hirao
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Manoor Prakash
authors.initials: MP
authors.lastname: Hande
authors.forename: Anne
authors.initials: A
authors.lastname: Hakem
authors.forename: Razqallah
authors.initials: R
authors.lastname: Hakem
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D064447:Checkpoint Kinase 2; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D018507:Gene Expression Regulation, Developmental; D042822:Genomic Instability; D008214:Lymphocytes / Q000166:cytology* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D064447:Checkpoint Kinase 2; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004720:Endonucleases; C498773:Mus81 protein, mouse