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Abstract
Disrupting the balance between self-renewal and differentiation of hematopoietic stem
cells (HSCs) leads to bone marrow failure or hematologic malignancy. However, how
HSCs sustain their quiescent state and avoid type I interferon (IFN)-mediated exhaustion
remains elusive. Here we defined a circular RNA that we named cia-cGAS that was highly
expressed in the nucleus of long-term (LT)-HSCs. Cia-cGAS deficiency in mice caused
elevated expression of type I IFNs in bone marrow and led to decreased numbers of
dormant LT-HSCs. Under homeostatic conditions, cia-cGAS bound DNA sensor cGAS in the
nucleus to block its synthase activity, thereby protecting dormant LT-HSCs from cGAS-mediated
exhaustion. Moreover, cia-cGAS harbored a stronger binding affinity to cGAS than self-DNA
did and consequently suppressed cGAS-mediated production of type I IFNs in LT-HSCs.
Our findings reveal a mechanism by which cia-cGAS inhibits nuclear cGAS by blocking
its enzymatic activity and preventing cGAS from recognizing self-DNA to maintain host
homeostasis.