Department of Molecular Genetics, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
J Cell Sci. 2010 Jun 15;123(Pt 12):2014-24. doi: 10.1242/jcs.063586. Epub 2010 May 25.
Many functional subdomains, including promyelocytic leukemia nuclear bodies (PML NBs), are formed in the mammalian nucleus. Various proteins are constitutively or transiently accumulated in PML NBs in a PML-dependent manner. MORC3 (microrchidia family CW-type zinc-finger 3), also known as NXP2, which consists of GHL-ATPase, a CW-type zinc-finger and coiled-coil domains, is localized in PML NBs, where it recruits and activates p53 to induce cellular senescence. Interestingly, we found that MORC3 can form PML-independent nuclear domains (NDs) in mouse hematopoietic cells and even in Pml-deficient cells. Here, we show that MORC3 colocalizes with PML by a two-step molecular mechanism: the PML-independent formation of MORC3 NDs by the ATPase cycle, and the association of MORC3 with PML via the SUMO1-SUMO-interacting motif (SIM). Similarly to other members of the GHL-ATPase family, MORC3 functions as a 'molecular clamp'. ATP binding induces conformational changes in MORC3, leading to the formation of MORC3 NDs, and subsequent ATP hydrolysis mediates the diffusion and binding of MORC3 to the nuclear matrix. MORC3 might clamp DNA or nucleosomes in MORC3 NDs via the CW domain. Furthermore, the SUMOylation of MORC3 at five sites was involved in the association of MORC3 with PML, and SUMO1-unmodified MORC3 formed NDs independently of PML.
许多功能亚域，包括早幼粒细胞白血病核体（PML NBs），在哺乳动物核中形成。各种蛋白质以依赖 PML 的方式在 PML NBs 中被持续或瞬时积累。MORC3（微幼虫家族 CW 型锌指 3），也称为 NXP2，由 GHL-ATPase、CW 型锌指和卷曲螺旋结构域组成，定位于 PML NBs 中，在那里它募集并激活 p53 以诱导细胞衰老。有趣的是，我们发现 MORC3 可以在小鼠造血细胞中甚至在 Pml 缺陷细胞中形成与 PML 无关的核域（NDs）。在这里，我们通过两步分子机制显示 MORC3 与 PML 共定位：ATP 酶循环诱导的 MORC3 NDs 的 PML 独立性形成，以及通过 SUMO1-SUMO 相互作用基序（SIM）与 MORC3 的关联。与 GHL-ATPase 家族的其他成员一样，MORC3 作为“分子夹”起作用。ATP 结合诱导 MORC3 的构象变化，导致 MORC3 NDs 的形成，随后 ATP 水解介导 MORC3 向核基质的扩散和结合。MORC3 可能通过 CW 结构域在 MORC3 NDs 中夹住 DNA 或核小体。此外，MORC3 的五个位点的 SUMO 化参与了 MORC3 与 PML 的关联，并且未修饰 SUMO1 的 MORC3 独立于 PML 形成 NDs。
