In this study, we identified the novel mechanism that RNaseH2A is transcriptionally regulated by E2Fs, thereby permitting rNMPs to promote genomic fragility via the downregulation of RNaseH2A during cellular senescence, leading to increased levels of genomic DNA fragments in the cytoplasm and the induction of SASP factors in senescent, progeroid and cancer cells (Fig. 8c). Here, RNASEH2A is linked to cancer.