SUV420H1能够对组蛋白H4赖氨酸20位点进行二甲基化和三甲基化修饰（H4K20me2/H4K20me3），在DNA复制、修复以及异染色质形成等过程中起到关键作用。此酶在多种癌症中发生失调。许多这些过程与其催化活性相关联。然而，删除和抑制SUV420H1显示出不同的表型，这表明该酶很可能具有未知的非催化活性。我们的低温电子显微镜（cryo-EM）、生化、生物物理和细胞分析揭示了SUV420H1如何识别其核小体底物，以及组蛋白变体H2A.Z如何刺激其催化活性。SUV420H1与核小体的结合导致核小体DNA与组蛋白八聚体的显著分离，这是一种非催化活性。我们假设这会调节大型高分子复合物对染色质的可及性。我们展示了SUV420H1可以促进染色质凝结，这是另一种我们推测其异染色质功能所需的非催化活性。综上所述，我们的研究揭示并描述了SUV420H1的催化和非催化机制，该关键组蛋白甲基转移酶在基因组稳定性中起到重要作用。© 2023 Elsevier Inc.版权所有。

SUV420H1 di- and tri-methylates histone H4 lysine 20 (H4K20me2/H4K20me3) and plays crucial roles in DNA replication, repair, and heterochromatin formation. It is dysregulated in several cancers. Many of these processes were linked to its catalytic activity. However, deletion and inhibition of SUV420H1 have shown distinct phenotypes, suggesting that the enzyme likely has uncharacterized non-catalytic activities. Our cryoelectron microscopy (cryo-EM), biochemical, biophysical, and cellular analyses reveal how SUV420H1 recognizes its nucleosome substrates, and how histone variant H2A.Z stimulates its catalytic activity. SUV420H1 binding to nucleosomes causes a dramatic detachment of nucleosomal DNA from the histone octamer, which is a non-catalytic activity. We hypothesize that this regulates the accessibility of large macromolecular complexes to chromatin. We show that SUV420H1 can promote chromatin condensation, another non-catalytic activity that we speculate is needed for its heterochromatin functions. Together, our studies uncover and characterize the catalytic and non-catalytic mechanisms of SUV420H1, a key histone methyltransferase that plays an essential role in genomic stability.Copyright © 2023 Elsevier Inc. All rights reserved.