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RPS27L (ribosomal protein S27-like) is an evolutionarily conserved ribosomal protein and a direct p53 target. We recently reported that  Rps27l  disruption triggers ribosomal stress to induce p53, causing postnatal death, which can be rescued by  Trp53   +/−  . Whether and how Rps27l modulates radiosensitivity is unknown. Here we report that  Rps27l   −/−   ; Trp53   +/−   mice are extremely sensitive to radiation due to reduced proliferation and massive induction of apoptosis in radiation-sensitive organs. Mechanistically, the radiation sensitivity is mediated by two signaling pathways: (1) activated p53 pathway due to imbalanced Mdm2/Mdm4 levels and reduced E3 ligase activity; and (2) reduced DNA damage response due to reduced MRN/Atm signal as a result of elevated Mdm2 binding of Nbs1 to inhibit Nbs1–Atm binding and subsequent Atm activation. Indeed, heterozygous deletion of  Mdm2  restores the MRN/Atm signal. Collectively, our study revealed a physiological condition under which Rps27l regulates the Mdm2/p53 and MRN/Atm axes to maintain DNA damage response and to confer radioprotection in vivo.

Inactivation of ribosomal protein S27-like confers radiosensitivity via the Mdm2-p53 and Mdm2–MRN–ATM axes