title: The Fanconi anemia pathway controls oncogenic response in hematopoietic stem and progenitor cells by regulating PRMT5-mediated p53 arginine methylation.
abstract: The Fanconi anemia (FA) pathway is involved in DNA damage and other cellular stress responses. We have investigated the role of the FA pathway in oncogenic stress response by employing an in vivo stress-response model expressing the Gadd45β-luciferase transgene. Using two inducible models of oncogenic activation (LSL-K-rasG12D and MycER), we show that hematopoietic stem and progenitor cells (HSPCs) from mice deficient for the FA core complex components Fanca or Fancc exhibit aberrant short-lived response to oncogenic insults. Mechanistic studies reveal that FA deficiency in HSPCs impairs oncogenic stress-induced G1 cell-cycle checkpoint, resulting from a compromised K-rasG12D-induced arginine methylation of p53 mediated by the protein arginine methyltransferase 5 (PRMT5). Furthermore, forced expression of PRMT5 in HSPCs from LSL-K-rasG12D/CreER-Fanca-/- mice prolongs oncogenic response and delays leukemia development in recipient mice. Our study defines an arginine methylation-dependent FA-p53 interplay that controls oncogenic stress response.
authors: Division of Experimental Hematology and Cancer Biology, Cincinnati, 45229 Ohio, USA.|Divisions of Radiation Health,College of Pharmacy, UAMS, Little Rock, 72205 Arkansas, USA.
authors: Wei
authors: W
authors: Du
authors: Division of Experimental Hematology and Cancer Biology, Cincinnati, 45229 Ohio, USA.
authors: Surya
authors: S
authors: Amarachintha
authors: Division of Experimental Hematology and Cancer Biology, Cincinnati, 45229 Ohio, USA.
authors: Ozlem
authors: O
authors: Erden
authors: Division of Experimental Hematology and Cancer Biology, Cincinnati, 45229 Ohio, USA.
authors: Andrew
authors: A
authors: Wilson
authors: Division of Experimental Hematology and Cancer Biology, Cincinnati, 45229 Ohio, USA.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, 45229 Ohio, USA.
authors: Qishen
authors: Q
authors: Pang
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D001120:Arginine / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D004249:DNA Damage; D005199:Fanconi Anemia / Q000235:genetics*; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D000943:Antigens, Differentiation; D001120:Arginine; D051856:Fanconi Anemia Complementation Group Proteins; D008156:Luciferases; D011484:Protein-Arginine N-Methyltransferases; D016159:Tumor Suppressor Protein p53; C086470:GADD45B protein, human; D000097642:GADD45 Proteins; C400529:PRMT5 protein, human
keywords: fanconi anemia; hematopoietic stem and progenitor cells; oncogenic stress; protein arginine methyltransferase 5 (PRMT5)