SCFFbxo22-KDM4A targets methylated p53 for degradation and regulates senescence

Abstract

Recent evidence has revealed that senescence induction requires fine-tuned activation of p53, however, mechanisms underlying the regulation of p53 activity during senescence have not as yet been clearly established. We demonstrate here that SCFFbxo22-KDM4A is a senescence-associated E3 ligase targeting methylated p53 for degradation. We find that Fbxo22 is highly expressed in senescent cells in a p53-dependent manner, and that SCFFbxo22 ubiquitylated p53 and formed a complex with a lysine demethylase, KDM4A. Ectopic expression of a catalytic mutant of KDM4A stabilizes p53 and enhances p53 interaction with PHF20 in the presence of Fbxo22. SCFFbxo22-KDM4A is required for the induction of p16 and senescence-associated secretory phenotypes during the late phase of senescence. Fbxo22−/− mice are almost half the size of Fbxo22+/− mice owing to the accumulation of p53. These results indicate that SCFFbxo22-KDM4A is an E3 ubiquitin ligase that targets methylated p53 and regulates key senescent processes.

Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity

“…However, the levels of p53 decline in some cells after they become senescent, sometimes to a level below the basal levels of p53 in non‐SnCs. This phenomenon was observed in keratinocytes (Kim et al, ), some human fibroblast cell lines (Johmura et al, ; Sisoula, Trachana, Patterson, & Gonos, ), and human prostate epithelial and uroepithelial cells (Schwarze, Shi, Fu, Watson, & Jarrard, ). These observations suggest that a sustained upregulation of p53 may not be required for the maintenance of senescence in some SnCs, probably because they express a high level of p16 which provides another barrier to prevent the escape of senescence (Beauséjour et al, ).…”

“…The downregulation of p53 after some cells become senescent may be in part attributable to the upregulation of C‐terminus of Hsp70‐interacting protein (CHIP) (Sisoula et al, ) and SCF Fbxo22 (Johmura et al, ) E3 ligases, which promote p53 ubiquitination and proteasome degradation. SCF Fbxo22 ‐mediated p53 downregulation may play an important role for the expression of SASP in these SnCs, because the expression of SASP depends on the activation of p38‐MAPK and NF‐κB; and p53 can suppress SASP via inhibiting p38‐MAPK activity and competing with NF‐κB for transcriptional cofactors (Johmura et al, ).…”

Beyond histones – the expanding roles of protein lysine methylation

“…These methylation events also facilitate the interaction of p53 with at least three MBDs in a methyl state‐specific manner ; for instance, p53(K382me1) is recognized by the MBT MBD repeat within the L3MBTL1 protein , whereas the p53(K382me2) is recognized by the tandem Tudor MBDs within both the PHF20 and 53BP1 proteins . Aside from the influence of both KMTs and MBDs, KDMs also play an important role in p53 regulation beyond the simple reversal of the methylation event; for instance, KDM4A demethylase has been found to be required for SCF Fbxo22 ‐dependent degradation of methylated p53 .…”

Sumoylation of the histone demethylase KDM4A is required for binding to tumor suppressor p53 in HCT116 colon cancer cell lines

“…Thus, it is possible that sumoylated KDM4A may negatively control p53 levels through enhancing MDM2-mediated p53 degradation. SCF FBXO22 ubiquitin ligase-KDM4A complexes regulate degradation of methylated p53, leading to control of senescence (Johmura et al 2016), which suggests a role for sumoylated KDM4A in SCF…”