While hyperactivity of EXO1 exonuclease activity in DNA mismatch-repair-deficient cancer cells was shown to activate the cGAS/STING pathway by induction of genome instability and consecutive mislocalization of chromatin to the cytosol (87), our findings strongly suggest 5’-flap cleavage during Okazaki fragment processing and/or during postreplicative ribonucleotide excision repair as the source of the pathogenic cGAS ligand accumulating in the absence of TREX1. The gene discussed is CGAS; the disease is cancer.