R-loop formation contributes to mTORC1 activation-dependent DNA replication stress induced by p53 deficiency

• p53 deficiency elevates DNA replication stress, evidenced by increased γH2AX expression and HPRT gene mutation rate. • Rapamycin, an mTORC1 inhibitor, alleviates replication stress in p53-knockout cells, implicating mTORC1 activation as a key mediator. • mTORC1 activation upregulates ribonucleotide reductase (RNR), promoting R-loop formation that contributes to replication stress. • The study highlights R-loops as a critical link between mTORC1 signaling and genome instability in p53-deficient contexts, offering potential therapeutic targets.