SPOP-containing complex regulates SETD2 stability and H3K36me3-coupled alternative splicing
Kun Zhu,Pin-Ji Lei,Lingao Ju,Xiang Wang,Kai Huang,Bo Yang,Changwei Shao,Yuan Zhu,Gang Wei,Xiang-Dong Fu,Xiang-Dong Fu,Lian-Yun Li,Min Wu +12 more
TLDR
The regulation of SETD2 protein stability by the proteasome system and the identification of SPOP, a key subunit of the CUL3 ubiquitin E3 ligase complex, as a SETD 2-interacting protein are reported.Abstract:
Trimethylation of histone H3K36 is a chromatin mark associated with active gene expression, which has been implicated in coupling transcription with mRNA splicing and DNA damage response. SETD2 is a major H3K36 trimethyltransferase, which has been implicated as a tumor suppressor in mammals. Here, we report the regulation of SETD2 protein stability by the proteasome system, and the identification of SPOP, a key subunit of the CUL3 ubiquitin E3 ligase complex, as a SETD2-interacting protein. We demonstrate that SPOP is critically involved in SETD2 stability control and that the SPOP/CUL3 complex is responsible for SETD2 polyubiquitination both in vivo and in vitro ChIP-Seq analysis and biochemical experiments demonstrate that modulation of SPOP expression confers differential H3K36me3 on SETD2 target genes, and induce H3K36me3-coupled alternative splicing events. Together, these findings establish a functional connection between oncogenic SPOP and tumor suppressive SETD2 in the dynamic regulation of gene expression on chromatin.read more
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Conflict of interest statement. None declared.
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Writing, erasing and reading histone lysine methylations
TL;DR: A more detailed understanding of histone lysine methylation is necessary for elucidating complex biological processes and, ultimately, for developing and improving disease treatments.
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Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis
Huairui Yuan,Ni Li,Da Fu,Jiale Ren,Jingyi Hui,Junjie Peng,Yongfeng Liu,Tong Qiu,Min Jiang,Qiang Pan,Ying Han,Xiaoming Wang,Qintong Li,Jun Qin +13 more
TL;DR: It is found that SETD2 counteracts Wnt signaling and its inactivation promotes intestinal tumorigenesis in mouse models of colorectal cancer (CRC) and ablation reduces intron retention of dishevelled segment polarity protein 2 (DVL2) pre-mRNA, thereby augmenting Wnt signalling.
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Shaping the cellular landscape with Set2/SETD2 methylation.
TL;DR: The latest insights into the functions of Set2/SETD2 in genome regulation and cancer development are summarized.
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Prostate Cancer-associated SPOP mutations enhance cancer cell survival and docetaxel resistance by upregulating Caprin1-dependent stress granule assembly
Qing Shi,Yasheng Zhu,Jian Ma,Kun Chang,Dongling Ding,Yang Bai,Kun Gao,Pingzhao Zhang,Ren Mo,Kai Feng,Xiaying Zhao,Liang Zhang,Huiru Sun,Dongyue Jiao,Y Chen,Yinghao Sun,Shimin Zhao,Haojie Huang,Yao Li,Shancheng Ren,Chenji Wang +20 more
TL;DR: SG assembly is aberrantly elevated in SPOP-mutated prostate cancer and the role of SPOP mutations in aberrant activation of the SG in prostate cancer is investigated and the relevanve of the mechanism in therapy resistance is explored.
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