On September 9th, the world-renowned academic journal Nucleic Acids Research (IF=9.202) published online the research paper by the team led by Professor Wu Min from School of Life Sciences at Wuhan University. It is discovered that E3 ubiquitin protein ligaseSPOP/CUL3 compound participates in the regulation and control of the alternative splicing of mRNA through the ubiquitination of histone methylation enzyme SETD2.

The paper is titled SPOP-containing complex regulates SETD2 stability and H3K36me3-coupled alternative splicing SPOP. Doctor Zhu Kun, Lei Pinji and Ju Lingao are the co-first authors of the paper, while professor Wu Min is the corresponding author. This research has gained supports from the National Ministry of Science and Technology, the National Natural Science Foundation of China and the Education Ministry's New Century Excellent Talents Plan.

SETD2 is the main histone H3K36me3 methylase in mammals’ cells, which takes part in the regulation and control of biological functions like DNA damage repair and alternative splicing of mRNA. Recent researches have shown that SETD2 is a key anti-oncogene, whose mutation is related to various kinds of cancers like renal carcinoma, leukemia and gliomas.

The researchers detect that E3 ubiquitin protein ligase SPOP/CUL3 compound and SETD2 have type-specific relations with each other. These reactions catalyze SETD2’s poly ubiquitin modification and promote the protein proteasome degradation of SETD2 protein. The research in the field of transcriptome and epigenetics further proves that SPOP-catalyzed SETD2 degradation occurs at a specific locus with gene-selective property. The degradation also leads to the reduction of histone H3K36me3 on specific genes and changes its mRNA’s alternative splicing status.

This research led to the first discovery of important anti-oncogene and E3 ubiquitin protein ligase of epigenetic modification enzyme SETD2 in mammals’ cells, and it also revealed the alternative splicing molecular regulation mechanism of mRNA. It has also illuminated the probable mechanisms of oncogeneSPOP, the key oncogene resulting in renal carcinoma, and anti-oncogene SETD2 during its rise.

(Translated by Wang Hanxu, edited by Jin Yiwen and Shen Yuxi, Hu Sijia)