Cereblon attenuates DNA damage-induced apoptosis by regulating the transcription-independent function of p53

Cereblon (CRBN) is the substrate receptor of the cullin 4-RING E3 ligase complex and has been employed for targeted protein degradation in the treatment of cancers. However, its normal physiological functions and molecular mechanism in the regulation of DNA damage response are largely unknown. Here we find that CRBN plays a protective role against DNA damage-induced apoptosis in cell lines and primary cells. Mechanistic studies demonstrate that although CRBN does not affect the ubiquitination and degradation of the tumor suppressor p53, it directly interacts with p53 and therefore, suppresses the interaction between p53 and anti-apoptotic regulators Bcl-2 and Bcl-XL. CRBN depletion enhances the interaction between p53 and Bcl-2/Bcl-XL, reduces mitochondrial membrane potential, increases the cleavage of caspase-3 and poly(ADP-ribose) polymerase 1, and thus promotes DNA damage-induced apoptosis in cell lines and primary cells upon etoposide treatment. Moreover, Crbn knockout mice exhibit increased mortality upon etoposide challenge. Taken together, our data elucidate a novel molecular mechanism by which CRBN inhibits DNA damage response in vitro and in vivo. This work extends our understanding of the broad spectrum of physiological roles for CRBN and may suggest its potential application in the treatment of DNA damage-associated diseases.