美国南加州大学洛杉矶分校Yali Dou研究组探明，非经典MLL1活性调控着丝粒相分离和基因组稳定性。2023年11月9日出版的《自然—细胞生物学》发表了这项成果。

他们发现MLL1/KMT2A在染色体乘客复合体(CPC)液-液相分离所必需的内在无序区域甲基化Borealin K143。该共晶结构突出了MLL1 SET结构域与Borealin K143的独特结合模式。抑制MLL1活性或使Borealin K143突变为精氨酸会干扰CPC相分离，降低极光激酶B活性，并损害着丝点-微管附着和姐妹染色单体内聚的解决。在肝细胞癌的一个亚群中，它们显著增加染色体不稳定性和非整倍体，导致生长抑制。这些结果表明，MLL1在通过非规范酶活性调节着丝粒内部液体凝聚和基因组稳定性方面具有非冗余功能。

据介绍，表观遗传失调是癌症的一个突出特征，如染色质调节因子的频繁突变，包括组蛋白甲基转移酶的MLL/KMT2家族。虽然MLL1/KMT2A对H3K4甲基化的活性有很好的文献记载，但它们的非规范活性大部分仍未被探索。

附：英文原文

Title: Non-canonical MLL1 activity regulates centromeric phase separation and genome stability

Author: Sha, Liang, Yang, Zi, An, Sojin, Yang, Wentao, Kim, Sungmin, Oh, Hoon, Xu, Jing, Yin, Jun, Wang, He, Lenz, Heinz-Josef, An, Woojin, Cho, Uhn-Soo, Dou, Yali

Issue&Volume: 2023-11-09

Abstract: Epigenetic dysregulation is a prominent feature in cancer, as exemplified by frequent mutations in chromatin regulators, including the MLL/KMT2 family of histone methyltransferases. Although MLL1/KMT2A activity on H3K4 methylation is well documented, their non-canonical activities remain mostly unexplored. Here we show that MLL1/KMT2A methylates Borealin K143 in the intrinsically disordered region essential for liquid–liquid phase separation of the chromosome passenger complex (CPC). The co-crystal structure highlights the distinct binding mode of the MLL1 SET domain with Borealin K143. Inhibiting MLL1 activity or mutating Borealin K143 to arginine perturbs CPC phase separation, reduces Aurora kinase B activity, and impairs the resolution of erroneous kinetochore–microtubule attachments and sister-chromatid cohesion. They significantly increase chromosome instability and aneuploidy in a subset of hepatocellular carcinoma, resulting in growth inhibition. These results demonstrate a non-redundant function of MLL1 in regulating inner centromere liquid condensates and genome stability via a non-canonical enzymatic activity. Sha et al. show that Borealin is a non-canonical methylation substrate for MLL1 that regulates phase separation of the inner centromeric chromosome passenger complex, and dictates genome integrity and tumour development in hepatocellular carcinoma.

DOI: 10.1038/s41556-023-01270-1

Source: https://www.nature.com/articles/s41556-023-01270-1