The Fanconi anemia pathway controls oncogenic response in hematopoietic stem and progenitor cells by regulating PRMT5-mediated p53 arginine methylation
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Wei Du1,2 , Surya Amarachintha1, Ozlem Erden1, Andrew Wilson1, Qishen Pang1,3
1Division of Experimental Hematology and Cancer Biology, Cincinnati, 45229 Ohio, USA
2Divisions of Radiation Health,College of Pharmacy, UAMS, Little Rock, 72205 Arkansas, USA
3Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, 45229 Ohio, USA
Qishen Pang, email: Qishen.firstname.lastname@example.org
Wei Du, email: email@example.com
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
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.
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