Abstract
The Set8/PR-Set7/KMT5a methyltransferase plays critical roles in governing transcriptional regulation, cell cycle progression and tumorigenesis. Although CRL4Cdt2 was reported to regulate Set8 stability, deleting the PIP motif only led to partial resistance to ultraviolet-induced degradation of Set8, indicating the existence of additional E3 ligase(s) controlling Set8 stability. Furthermore, it remains largely undefined how DNA damage-induced kinase cascades trigger the timely destruction of Set8 to govern tumorigenesis. Here, we report that SCFβ-TRCP earmarks Set8 for ubiquitination and degradation in a casein kinase I-dependent manner, which is activated by DNA-damaging agents. Biologically, both CRL4Cdt2 and SCFβ-TRCP-mediated pathways contribute to ultraviolet-induced Set8 degradation to control cell cycle progression, governing the onset of DNA damage-induced checkpoints. Therefore, like many critical cell cycle regulators including p21 and Cdt1, we uncover a tight regulatory network to accurately control Set8 abundance. Our studies further suggest that aberrancies in this delicate degradation pathway might contribute to aberrant elevation of Set8 in human tumours.
Highlights
The Set8/PR-Set7/KMT5a methyltransferase plays critical roles in governing transcriptional regulation, cell cycle progression and tumorigenesis
We report that Set[8] is an ubiquitin substrate of b-TRCP (b-transducin repeatcontaining protein), and Set[8] ubiquitination and subsequent degradation is timely governed by the E3 ubiquitin ligase SCFb-TRCP in a casein kinase I (CKI)-dependent manner
We further demonstrated that the interaction of b-TRCP1 and Set[8] was significantly reduced using a b-TRCP1 mutant (R474A) harbouring a point mutation within the substrate interaction site of b-TRCP1
Summary
The Set8/PR-Set7/KMT5a methyltransferase plays critical roles in governing transcriptional regulation, cell cycle progression and tumorigenesis. Post-translational modifications of histones play a critical role in a number of cellular processes such as mitosis, meiosis and the DNA damage response[1] These modifications include methylation, acetylation, phosphorylation and ubiquitination, which often occur on the N-terminal tails of histone proteins. As Set[8] plays an important role in various cellular processes, its activity needs to be tightly regulated for the precise control of cell fate To this end, a wealth of evidence has revealed that Set[8] could be regulated at both the transcriptional level[6] and by post-translational modification(s)[1]. Our current study supports a pivotal role of b-TRCP in CKI-mediated Set[8] degradation, and further implies that targeting b-TRCP could be a novel approach to govern cell cycle progression in part by regulating Set[8] destruction
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