Differential response of Fanconi anemia hematopoietic stem and progenitor cells to oxidative and oncogenic stresses

Abstract

Members of the Fanconi anemia (FA) pathway are involved in DNA damage response. By employing an in vivo stress-response model expressing the Gadd45b-luciferase transgenic cassett, we show here that hematopoietic stem and progenitor cells (HSPCs) from mice deficient for the FA gene Fanca or Fancc differentially responded to oxidative and oncogenic stresses. Compared to wild-type controls, Fanca-/- or Fancc-/- HSPCs exhibited a persistent response to oxidative stress. Mechanistically, we demonstrated that accumulation of unrepaired DNA damage, particularly in oxidative damage-sensitive genes, was responsible for the long-lasting response in FA HSPCs. In contrast, using two inducible models of oncogenic activation (LSL-K-rasG12D and MycER), we identify a short-lived response of FA HSPCs to oncogenic insults. Loss of Fanca or Fancc impaired oncogenic stress-induced senescence (OIS), and genetic correction of Fanca or Fancc deficiency restored OIS in HSPCs. Furthermore, FA deficiency compromised K-rasG12D-induced arginine methylation of p53 mediated by PRMT5. Finally, forced expression of PRMT5 in HSPCs from Fanca-/-;K-rasG12D mice prolonged oncogenic response and delayed leukemia development in recipient mice. Taken together, our study demonstrates differential responses of HSPCs to oxidative and oncogenic stresses and identifies the FA pathway as an integral part of this versatile cellular mechanism.