学位論文内容の要旨（ Summary of dissertation ）博士の専攻分野の名称

博士（医 学）（Degree conferred: Doctor of Philosophy）

氏 名迪丽努尔 艾尼瓦尔（Name of recipient: Delnur Anwar ）学 位 論 文 題 名（Title of dissertation）
p53 represses the transcription of snRNA genes by preventing the formation of little elongationcomplex（p53 は little elongation complex の形成を阻害することによって snRNA 遺伝子の転写を抑制する）【Background and Objectives】
The regulation of transcription by RNA polymerase II (Pol II) plays a very importantrole in a variety of cellular functions. ELL/EAF containing little elongation complex(LEC) was identified to be required for the transcription of Pol II-dependent small
nuclear RNA (snRNA) genes. It was known that tumor suppressor p53 is a specificinteractor of ELL inhibits the transcription elongation activity of ELL. Here we provide
evidence that p53 inhibits the interaction between EAF/ELL and ICE1 in LEC, so that
p53 represses the transcription of Pol II-dependent snRNA genes through inhibiting
LEC function. Induction of p53 triggered by ultraviolet (UV) decreased the occupancy ofICE1 at the Pol II-dependent snRNA genes. Consistent with the results, knockdown ofp53 increased both the expression of snRNA genes and the occupancy of Pol II and thecomponents of LEC at snRNA genes. Our results indicate that p53 interferes with theinteraction between ELL/EAF and ICE1 and represses transcription of snRNA genes byPol II.
【Materials and Methods】
In this study HCT116 cells were mainly used for experimental data. We usedbiochemical methods for example immunoprecipitation (IP), siRNA transfection,
western blotting and chromatin IP (ChIP).
【Results】
In our previous work we proved that EAF1 is responsible and directly bound tohuman mediator subunit Med26-N-terminal domain. In this thesis we included thebinding region of EAF1 for Med26-N-terminus domain, which is the C-terminal
amino-acid residue from 245 to 268 in human EAF1. We also found out that the EAF

family member protein functions as an adaptor molecule to connect Med26 and LEC.
ICE1 (KIAA0947) functions as a core subunit of LEC and interacts with both ICE2
(NARG2) and ELL/EAF. And the C-terminal fragment of ICE1 (1191-2266) is requiredfor the formation of LEC. We here proved that depletion of EAF1 decrease theoccupancy of ICE1 at a subset snRNA genes. Therefore we proved a model that EAF1functions as an adaptor molecule connecting LEC and Med26 at a subset of Pol II
dependent snRNA genes. In this study, we showed that EAF1 is required for therecruitment of ICE1 to a subset of RNA Pol II-dependent snRNA genes. We providea putative model that EAF1 functions as an adaptor molecule connecting LEC andMED26 at a subset of Pol II dependent snRNA genes. Our model proposes that p53
interacts with ELL and inhibits the interaction between ELL and ICE1, leading tothe repression of the formation of LEC at snRNA genes. p53 induced by UV
decreased the occupancy of ICE1 at the Pol II-dependent snRNA genes. Moreover,
p53 repressed the occupancy of not only Pol II but also ICE1 at snRNA gene,
resulting in downregulation of Pol II-dependent snRNA genes. Taken together, p53
likely decreases the transcription of a subset of Pol II-dependent snRNA genes via
interaction with ELL.
【Discussion】
Our study suggests that tumor suppresser p53 regulates transcription of Pol
II-dependent snRNA genes through inhibiting LEC function. Tp53 has been shown to be
mutated or lost in more than 50% cancers. Our study proposes a new model that p53
regulates transcription of snRNA genes through inhibiting transcription elongation
factors such as ELL/EAF and/or LEC and contributes to a new aspect of p53 function incancer and diseases which associates with dysregulation of snRNA genes transcription.
【Conclusion】

Taken together, p53 regulates transcription of Pol II-dependent snRNA genes
through inhibiting the function of LEC. p53 genes has been shown to be mutated orlost in more than 50% cancers. Therefore, our study proposes a new model that p53
regulates transcription of snRNA genes through inhibiting transcription elongation
factors such as ELL/EAF and/or LEC and may contribute to an understanding of
diseases which associates with dysregulation of snRNA genes transcription.