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히스톤 H4R3의 이중메틸화와 히스톤 탈아세틸화에 의한 세포의 형태적 조절

Title
히스톤 H4R3의 이중메틸화와 히스톤 탈아세틸화에 의한 세포의 형태적 조절
Author
단여신
Alternative Author(s)
Ruxin Duan
Advisor(s)
안성훈
Issue Date
2018-08
Publisher
한양대학교
Degree
Doctor
Abstract
Protein arginine methylation, an evolutionarily conserved post-translational modification, has an involvement in multiple cellular functions, including transcriptional regulation, DNA damage repair, RNA metabolism and signal transduction. Protein arginine methylation is catalyzed by a family of enzymes named PRMTs (protein arginine methyltransferases) by transferring a methyl group to a variety of substrates including histones and transcription factors. In budding yeast, Hsl7 (histone synthetic lethal 7) displays a type II PRMT activity in vitro by generating symmetric dimethylarginine residues on histone H2A or, to a relatively poor degree, on histone H4 and bovine myelin basic protein. A well-studied pathway regulated by Hsl7 is the morphogenesis checkpoint mechanism in which kinase Hsl1 recruits Hsl7 to septin ring and phosphorylates Swe1 for degradation following by the activation of cyclin-dependent kinase Cdc28 to promote the G2/M transition. However, it is largely unknown what is the in vivo substrate of Hsl7 and how it contributes to the important cellular processes via its methylation activity. In this study, I provide evidences that Hsl7 is responsible for in vivo symmetric dimethylation on histone H4 arginine 3 (H4R3me2s). I found that histone H4R3, the substrate of Hsl7, is genetically related to the histone deacetylase (HDAC) Rpd3. I also observed that low level of H4R3me2s is maintained by the Rpd3-mediated histone deacetylation, at least on H4K5, in a global level and also at the transcriptionally repressed chromatin region. But, contrary to the expectation, the association of Rpd3 with the repressed chromatin is not influenced by the point mutants at H4R3 in which the symmetric dimethylation on H4R3 is disrupted by the alanine (H4R3A) or lysine (H4R3K) substitution. Next, I determined the role of Hsl7 in morphogenesis control and confirmed that the Hsl7 maintains the normal cell morphology and localizes at the bud neck only during the G2/M phase of the cell cycle. Fluorescent microscope assay suggests that the accumulation of H4R3me2s induced by rpd3Δ or H4K5Q is not concomitant with the subcellular relocalization of Hsl7. However, significantly, the apical growth by hsl7Δ or H4R3K is aggravated by treatment with a HDAC inhibitor in a dosage-dependent manner, suggesting that the hyperacetylation state of histones has functionally connected to the role of histone dimethylation by Hsl7 in regulating the proper asymmetric cell growth. Additionally, the observation that the elongated cell shape in H4R3K is not further affected by the deletion of RPD3 implies that other histone deacetylases besides Rpd3 are involved in the Hsl7-regulated morphology. Taken together, the findings in this study provide new insight into the epigenetic modification important for cell cycle morphogenesis checkpoint control based on the repressive histone crosstalk between the symmetric arginine methylation of H4R3 by Hsl7 and histone deacetylation by HDAC.
URI
http://dcollection.hanyang.ac.kr/common/orgView/000000106357http://repository.hanyang.ac.kr/handle/20.500.11754/75665
Appears in Collections:
GRADUATE SCHOOL[S](대학원) > MOLECULAR & LIFE SCIENCE(분자생명과학과) > Theses (Ph.D.)
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