Abstract
Members of the Fanconi anemia (FA) protein family are involved in DNA damage response. A common damage to DNA in vivo is oxidative stress, and compelling evidence suggests that FA cells are in an in vivo pro-oxidant state. In response to oncogenic activation, normal cells induce genetically encoding programs that prevent deregulated proliferation and thus protect multicellular organisms from cancer progression. How FA cells respond to oxidative DNA damage and oncogenic stress is largely unknown. By employing an in vivo stress-response model expressing the Gadd45b-luciferase transgene, 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 both in vitro and in vivo. Mechanistic studies revealed that 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 the protein arginine methyltransferase 5 (PRMT5). Finally, forced expression of PRMT5 in HSPCs from LSL-K-rasG12D/CreER-Fanca-/- 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.
Disclosures
No relevant conflicts of interest to declare.
The Sirt1 activator SRT3025 expands hematopoietic stem and progenitor cells and improves hematopoiesis in Fanconi anemia mice
