Clearance of genome-damaged cells from the hematopoietic system via p53 without contribution by the cGAS/STING axis

Abstract

Cell-intrinsic response patterns control risks arising from genome-damaged cells, preventing malignant transformation. p53-dependent DNA damage responses halt the cell cycle and induce either repair, senescence or cell death. Cyclic-GMP-AMP synthase (cGAS) has emerged as a new principle detecting genome damage and activating complex response programs. This DNA sensor is activated by micronuclei, chromosome bridges and prolonged mitotic arrest. STING-responses downstream of cGAS can drive cells into senescence or cell death through the induction of antiproliferative type I interferons (IFN) and proapoptotic tumor necrosis factor. Herein, we investigated how DNA damage-dependent and DNA-damage independent chronic activation of cGAS/STING signaling impacts on hematopoiesis. Hematopoietic loss of ribonucleotide excision repair (RER) resulted in chromosomal instability and activation of the cGAS/STING/IFN axis. Mice with hematopoietic RER-deficiency displayed compromised hematopoietic stem cell (HSC) function resulting in cytopenia and ultimately developed leukemia. Additional loss of p53 largely rescued mature blood cell production at the cost of accelerated leukemogenesis, while concurrent loss of cGAS, STING or type I IFN signalling had no detectable effect on HSC function, cytopenia and leukemia development in RER-deficient hematopoiesis. Also in models of acute genome damage, cGAS was irrelevant for the initial cell loss as well as the subsequent recovery of hematopoiesis. In contrast, a constitutive STING gain-of-function mutation impaired HSC functions independently of DNA damage. Collectively, we present in vivo evidence that the cGAS/STING pathway does not influence the capacity of the hematopoietic system to cope with DNA damage. Nevertheless, chronic activation of STING dramatically reduced the fitness of HSCs.