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The Fanconi anemia pathway controls oncogenic response in hematopoietic stem and progenitor cells by regulating PRMT5-mediated p53 arginine methylation

2016; Impact Journals LLC; Volume: 7; Issue: 37 Linguagem: Inglês

10.18632/oncotarget.11088

1949-2553

Wei Du, Surya Amarachintha, Ozlem Erden, Andrew Wilson, Qishen Pang,

Sex work and related issues

// Wei Du 1, 2 , Surya Amarachintha 1 , Ozlem Erden 1 , Andrew Wilson 1 , Qishen Pang 1, 3 1 Division of Experimental Hematology and Cancer Biology, Cincinnati, 45229 Ohio, USA 2 Divisions of Radiation Health,College of Pharmacy, UAMS, Little Rock, 72205 Arkansas, USA 3 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, 45229 Ohio, USA Correspondence to: Qishen Pang, email: Qishen.pang@cchmc.org Wei Du, email: wdu@uams.edu Keywords: fanconi anemia, hematopoietic stem and progenitor cells, oncogenic stress, protein arginine methyltransferase 5 (PRMT5) Received: October 13, 2015 Accepted: July 26, 2016 Published: August 05, 2016 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-ras G12D and Myc ER ), 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 G 1 cell-cycle checkpoint, resulting from a compromised K-ras G12D -induced arginine methylation of p53 mediated by the protein arginine methyltransferase 5 (PRMT5). Furthermore, forced expression of PRMT5 in HSPCs from LSL-K-ras G12D /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.