Cla4 phosphorylates histone methyltransferase Set1 to prevent its degradation by the APC/CCdh1 complex
- PMID: 37774018
- PMCID: PMC10541012
- DOI: 10.1126/sciadv.adi7238
Cla4 phosphorylates histone methyltransferase Set1 to prevent its degradation by the APC/CCdh1 complex
Abstract
H3K4 trimethylation (H3K4me3) is a conserved histone modification catalyzed by histone methyltransferase Set1, and its dysregulation is associated with pathologies. Here, we show that Set1 is intrinsically unstable and elucidate how its protein levels are controlled within cell cycle and during gene transcription. Specifically, Set1 contains a destruction box (D-box) that is recognized by E3 ligase APC/CCdh1 and degraded by the ubiquitin-proteasome pathway. Cla4 phosphorylates serine 228 (S228) within Set1 D-box, which inhibits APC/CCdh1-mediated Set1 proteolysis. During gene transcription, PAF complex facilitates Cla4 to phosphorylate Set1-S228 and protect chromatin-bound Set1 from degradation. By modulating Set1 stability and its binding to chromatin, Cla4 and APC/CCdh1 control H3K4me3 levels, which then regulate gene transcription, cell cycle progression, and chronological aging. In addition, there are 141 proteins containing the D-box that can be potentially phosphorylated by Cla4 to prevent their degradation by APC/CCdh1. We addressed the long-standing question about how Set1 stability is controlled and uncovered a new mechanism to regulate protein stability.
Figures
![Fig. 1.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10541012/bin/sciadv.adi7238-f1.gif)
![Fig. 2.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10541012/bin/sciadv.adi7238-f2.gif)
![Fig. 3.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10541012/bin/sciadv.adi7238-f3.gif)
![Fig. 4.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10541012/bin/sciadv.adi7238-f4.gif)
![Fig. 5.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10541012/bin/sciadv.adi7238-f5.gif)
![Fig. 6.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10541012/bin/sciadv.adi7238-f6.gif)
![Fig. 7.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10541012/bin/sciadv.adi7238-f7.gif)
Similar articles
-
Cdh1 degradation is mediated by APC/C-Cdh1 and SCF-Cdc4 in budding yeast.Biochem Biophys Res Commun. 2018 Dec 2;506(4):932-938. doi: 10.1016/j.bbrc.2018.10.179. Epub 2018 Nov 2. Biochem Biophys Res Commun. 2018. PMID: 30396569
-
The KEN box: an APC recognition signal distinct from the D box targeted by Cdh1.Genes Dev. 2000 Mar 15;14(6):655-65. Genes Dev. 2000. PMID: 10733526 Free PMC article.
-
Substrate Recognition by the Cdh1 Destruction Box Receptor Is a General Requirement for APC/CCdh1-mediated Proteolysis.J Biol Chem. 2016 Jul 22;291(30):15564-74. doi: 10.1074/jbc.M116.731190. Epub 2016 May 23. J Biol Chem. 2016. PMID: 27226622 Free PMC article.
-
Insights into the cellular mechanism of the yeast ubiquitin ligase APC/C-Cdh1 from the analysis of in vivo degrons.Mol Biol Cell. 2015 Mar 1;26(5):843-58. doi: 10.1091/mbc.E14-09-1342. Epub 2014 Dec 24. Mol Biol Cell. 2015. PMID: 25540434 Free PMC article.
-
Structure, function and mechanism of the anaphase promoting complex (APC/C).Q Rev Biophys. 2011 May;44(2):153-90. doi: 10.1017/S0033583510000259. Epub 2010 Nov 22. Q Rev Biophys. 2011. PMID: 21092369 Review.
References
-
- Kouzarides T., Chromatin modifications and their function. Cell 128, 693–705 (2007). - PubMed
-
- Yuan H., Han Y., Wang X., Li N., Liu Q., Yin Y., Wang H., Pan L., Li L., Song K., Qiu T., Pan Q., Chen Q., Zhang G., Zang Y., Tan M., Zhang J., Li Q., Wang X., Jiang J., Qin J., SETD2 restricts prostate cancer metastasis by integrating EZH2 and AMPK signaling pathways. Cancer Cell 38, 350–365.e7 (2020). - PubMed
-
- Derr R. S., van Hoesel A. Q., Benard A., Goossens-Beumer I. J., Sajet A., Dekker-Ensink N. G., de Kruijf E. M., Bastiaannet E., Smit V. T. H. B. M., van de Velde C. J. H., Kuppen P. J. K., High nuclear expression levels of histone-modifying enzymes LSD1, HDAC2 and SIRT1 in tumor cells correlate with decreased survival and increased relapse in breast cancer patients. BMC Cancer 14, 604 (2014). - PMC - PubMed
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Molecular Biology Databases
Miscellaneous