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Cla4 phosphorylates histone methyltransferase Set1 to prevent its degradation by the APC/C(Cdh1) complex
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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541012/ https://www.ncbi.nlm.nih.gov/pubmed/37774018 http://dx.doi.org/10.1126/sciadv.adi7238 |
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author | Gong, Xuanyunjing Wang, Shanshan Yu, Qi Wang, Min Ge, Feng Li, Shanshan Yu, Xilan |
author_facet | Gong, Xuanyunjing Wang, Shanshan Yu, Qi Wang, Min Ge, Feng Li, Shanshan Yu, Xilan |
author_sort | Gong, Xuanyunjing |
collection | PubMed |
description | 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/C(Cdh1) and degraded by the ubiquitin-proteasome pathway. Cla4 phosphorylates serine 228 (S228) within Set1 D-box, which inhibits APC/C(Cdh1)-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/C(Cdh1) 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/C(Cdh1). We addressed the long-standing question about how Set1 stability is controlled and uncovered a new mechanism to regulate protein stability. |
format | Online Article Text |
id | pubmed-10541012 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-105410122023-10-01 Cla4 phosphorylates histone methyltransferase Set1 to prevent its degradation by the APC/C(Cdh1) complex Gong, Xuanyunjing Wang, Shanshan Yu, Qi Wang, Min Ge, Feng Li, Shanshan Yu, Xilan Sci Adv Biomedicine and Life Sciences 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/C(Cdh1) and degraded by the ubiquitin-proteasome pathway. Cla4 phosphorylates serine 228 (S228) within Set1 D-box, which inhibits APC/C(Cdh1)-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/C(Cdh1) 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/C(Cdh1). We addressed the long-standing question about how Set1 stability is controlled and uncovered a new mechanism to regulate protein stability. American Association for the Advancement of Science 2023-09-29 /pmc/articles/PMC10541012/ /pubmed/37774018 http://dx.doi.org/10.1126/sciadv.adi7238 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Gong, Xuanyunjing Wang, Shanshan Yu, Qi Wang, Min Ge, Feng Li, Shanshan Yu, Xilan Cla4 phosphorylates histone methyltransferase Set1 to prevent its degradation by the APC/C(Cdh1) complex |
title | Cla4 phosphorylates histone methyltransferase Set1 to prevent its degradation by the APC/C(Cdh1) complex |
title_full | Cla4 phosphorylates histone methyltransferase Set1 to prevent its degradation by the APC/C(Cdh1) complex |
title_fullStr | Cla4 phosphorylates histone methyltransferase Set1 to prevent its degradation by the APC/C(Cdh1) complex |
title_full_unstemmed | Cla4 phosphorylates histone methyltransferase Set1 to prevent its degradation by the APC/C(Cdh1) complex |
title_short | Cla4 phosphorylates histone methyltransferase Set1 to prevent its degradation by the APC/C(Cdh1) complex |
title_sort | cla4 phosphorylates histone methyltransferase set1 to prevent its degradation by the apc/c(cdh1) complex |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541012/ https://www.ncbi.nlm.nih.gov/pubmed/37774018 http://dx.doi.org/10.1126/sciadv.adi7238 |
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