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

Abstract

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.

Caspase-8 Inhibition Prevents the Cleavage and Degradation of E3 Ligase Substrate Receptor Cereblon and Potentiates Its Biological Function

“…Recently, it has been discovered that CRBN inhibits DNA damage-induced apoptosis (Zhou and Xu, 2019). However, it is unknown whether and how death receptors regulate CRBN and its function.…”

“…Because activated CASP-8 could cleave BID (Li et al, 1998;Luo et al, 1998), BID cleavage or reduction could serve as an indicator to demonstrate the activation of death receptor and CASP-8 (Chou et al, 1999). In our previous study, we found that CRBN inhibits the etoposide-induced intrinsic apoptosis (Zhou and Xu, 2019). However, it is unknown whether CRBN is involved in the death receptor-induced extrinsic apoptotic pathway and whether modulation of caspase activity could regulate the biological function of CRBN.…”

Ablation of CRBN induces loss of type I collagen and SCH in mouse skin by fibroblast senescence via the p38 MAPK pathway

“…CRBN KO mice have been characterized in multiple phenotypical contexts. A series of studies elucidating the physiological function of CRBN has also been reported in various disease models or under specific challenges [ 15 , 24 , 29 – 31 ]. The deficiency of CRBN has exhibited protective effects or positive influence under various adverse challenges in vivo .…”

“…The silencing of CRBN impaired the ability of lenalidomide to induce p21 expression, indicating that lenalidomide directly inhibits CLL cell proliferation in a CRBN/p21-dependent manner [ 23 ]. Recently, p53 was reported to be a direct substrate of CRBN, yet subcellular distribution, protein expression level, and ubiquitination were not significantly affected [ 24 ]. In the interim, our research group reported that the permanent cell line of mouse embryonic fibroblast (MEF) that lacked CRBN was strongly resistant to hydrogen peroxide (H 2 O 2 ), which is a typical ROS inducer for activating cellular senescence, and the loss of CRBN exhibited the pre-activation of p38 MAPK [ 25 ].…”

Long-term depletion of cereblon induces mitochondrial dysfunction in cancer cells

“…These findings suggest that CRBN can control mitochondrial homeostasis through regulating ECSIT, which is essential for stabilization of mitochondrial complex I and ROS. Furthermore, CRBN binds p53 and hinders its interactions with the anti-apoptotic mitochondrial protein B-cell lymphoma 2/B-cell lymphoma-extra Large (Bcl-2/Bcl-xL) ( 13 ). Overall, the above results support the theory that CRBN prevents oxidative damage-induced cell death through facilitating maintenance of mitochondrial homeostasis.…”