중심체에서 히스톤 탈아세틸화 효소와 E3 유비퀴틴 중합효소의 기능 연구

Abstract

A centrosome consists of a pair of centrioles surrounded by pericentriolar materials (PCMs). During the cell cycle, the centrosome plays diverse roles in organizing cytoplasmic microtubules in interphase, assembling the mitotic spindle during mitosis and forming the cilium in quiescent cells. To carry out these functions, centrosomal proteins undergo diverse modifications such as phosphorylation, acetylation/deacetylation, and ubiquitination/deubiquitination. Here, I investigated the function of histone deacetylases in ciliogenesis and E3 ubiquitin (Ub) ligases in the regulation of centrosome duplication. In chapter 1, I examined the function of class Ⅰ histone deacetylases (HDACs) in cilia assembly and elongation. HDACs are originally known to regulate gene transcription by deacetylating the histones. However, HDACs are also known to target and deacetylate non-histone proteins, thereby affecting their activities and functions. It has been known that HDAC1, 4, 10, 11 and SIRT1, 2 are localized to the centrosome and among them, HDAC1, HDAC5 and SIRT1 are involved in the suppression of centrosome amplification and HDAC6 is implicated in cilia disassembly. However, no HDAC has been identified as a positive regulator of ciliogenesis yet. Thus, I examined the role of class Ⅰ HDACs in the cilium assembly and elongation. The results revealed that HDAC3 and 8 are required for the assembly and elongation of the cilium. In chapter 2, I investigated the function of E3 Ub ligases located at the centrosome among 226 E3 ubiquitin ligases. Selected centrosomal proteins should be synthesized and degraded during the cell cycle. E3 Ub ligases are responsible for drastic degradation of centrosomal proteins during centrosome duplication Here, I identified E3 Ub ligases located in the centrosome. Among 226 E3 ligases, I found that 31 E3 ligases are located in the centrosome. Furthermore, I observed that FBXO31, a component of the SCF ubiquitination complex, is involved in the suppression of centrosome amplification in U2OS cells. On the other hand, ANAPC11, FBXL14, FBXO4, HERC3, KLHL2, PELI1, RNF135, SPSB4, and TCEB2 were implicated in the promotion of centrosome amplification.