Unit of Molecular Genetics of Aging, Department of Ecology and Biology (DEB), University of Tuscia, 01100 Viterbo, Italy.
Faculty of Biomedical Sciences, Institute of Oncology Research, USI, Bellinzona, TI, 6500, Switzerland.
Eur J Cell Biol. 2023 Jun;102(2):151325. doi: 10.1016/j.ejcb.2023.151325. Epub 2023 May 19.
Mutations in CSA and CSB proteins cause Cockayne syndrome, a rare genetic neurodevelopment disorder. Alongside their demonstrated roles in DNA repair and transcription, these two proteins have recently been discovered to regulate cytokinesis, the final stage of the cell division. This last finding allowed, for the first time, to highlight an extranuclear localization of CS proteins, beyond the one already known at mitochondria. In this study, we demonstrated an additional role for CSA protein being recruited at centrosomes in a strictly determined step of mitosis, which ranges from pro-metaphase until metaphase exit. Centrosomal CSA exerts its function in specifically targeting the pool of centrosomal Cyclin B1 for ubiquitination and proteasomal degradation. Interestingly, a lack of CSA recruitment at centrosomes does not affect Cyclin B1 centrosomal localization but, instead, it causes its lasting centrosomal permanence, thus inducing Caspase 3 activation and apoptosis. The discovery of this unveiled before CSA recruitment at centrosomes opens a new and promising scenario for the understanding of some of the complex and different clinical aspects of Cockayne Syndrome.
CSA 和 CSB 蛋白的突变会导致 Cockayne 综合征，这是一种罕见的遗传性神经发育障碍。这两种蛋白除了在 DNA 修复和转录中表现出的作用外，最近还被发现可以调节胞质分裂，即细胞分裂的最后阶段。这一最新发现首次揭示了 CS 蛋白的核外定位，超出了已知的线粒体定位。在这项研究中，我们证明了 CSA 蛋白在有丝分裂的一个严格确定的步骤中被招募到中心体，这个步骤从前期到中期退出。中心体上的 CSA 发挥作用，特异性地针对中心体 Cycin B1 池进行泛素化和蛋白酶体降解。有趣的是，中心体上 CSA 的缺失不会影响 Cycin B1 的中心体定位，而是导致其持久的中心体存在，从而诱导 Caspase 3 的激活和细胞凋亡。在 CSA 被招募到中心体之前的这一发现，为理解 Cockayne 综合征的一些复杂和不同的临床方面开辟了一个新的、有希望的场景。
