Article
Multidisciplinary Sciences
Tasniem Fetian, Brendan M. McShane, Nicole L. Horan, Donya N. Shodja, Jason D. True, Amber L. Mosley, Karen M. Arndt
Summary: Histone modifications coupled to transcription elongation play important roles in regulating gene expression. The Paf1 transcription elongation complex (Paf1C) interacts with the ubiquitin conjugase Rad6 through its histone modification domain (HMD), leading to H2BK123 ubiquitylation. The specific interface between a transcription elongation factor and a ubiquitin conjugase guides substrate selection during active gene expression.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Yan Qin, Yuqiao Zhou, Yinghua Cao, Yanpeng Ren, Pujuan Deng, Junyi Jiang, Zhanxin Wang
Summary: The multicomponent PAF1C is an important transcription elongation factor that regulates genome-wide transcription. In this study, the structural core of the yeast PAF1C was evaluated, and the interaction details among its components were observed. A new binding surface of Rtf1 on PAF1C was identified, and the C-terminal sequence of Rtf1 was found to have changed during evolution. This work provides a precise model of PAF1C and enhances our understanding of its molecular mechanism and in vivo function.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Genetics & Heredity
Margaret K. Shirra, Rachel A. Kocik, Mitchell A. Ellison, Karen M. Arndt
Summary: Maintenance of chromatin structure during transcription elongation requires cooperation among regulatory factors, with histone post-translational modifications playing a key role. The Paf1 transcription elongation complex, in coordination with Hda1C and the H2B ubiquitylation pathway, helps regulate chromatin structure and support chromatin accessibility during transcription elongation.
G3-GENES GENOMES GENETICS
(2021)
Article
Cardiac & Cardiovascular Systems
Adam D. Langenbacher, Fei Lu, Lauren Crisman, Zi Yi Stephanie Huang, Douglas J. Chapski, Thomas M. Vondriska, Yibin Wang, Chen Gao, Jau-Nian Chen
Summary: In this study, the importance of Rtf1 in neonatal and adult cardiomyocytes was investigated through knockdown and knockout approaches. The results showed that loss of Rtf1 activity disrupted cell morphology, sarcomeres, cell-cell junctions, and led to fibrosis and systolic dysfunction. Moreover, Rtf1 knockout hearts exhibited structural and gene expression defects resembling dilated cardiomyopathy, indicating that Rtf1 is continuously required for the expression of the cardiac gene program.
JOURNAL OF CARDIOVASCULAR DEVELOPMENT AND DISEASE
(2023)
Article
Genetics & Heredity
Sarah Mackinnon, Viviane Page, Jennifer J. Chen, Ali Shariat-Panahi, Ryan D. Martin, Terence E. Hebert, Jason C. Tanny
Summary: Heterochromatin is a condensed chromatin structure that represses transcription, and its establishment requires transcription of heterochromatic sequences. In the model eukaryote Schizosaccharomyces pombe, the RNA polymerase II processivity factor Spt5 negatively regulates heterochromatin through its C-terminal domain. The phosphorylation and length of the Spt5 C-terminal domain have distinct regulatory effects on heterochromatin formation.
Article
Biochemistry & Molecular Biology
Feilong Chen, Beibei Liu, Jianwei Zeng, Lu Guo, Xuan Ge, Wei Feng, De-Feng Li, Hao Zhou, Jiafu Long
Summary: In this study, the crystal structure of the core module of the PAF1C complex in Saccharomyces cerevisiae was determined, revealing the interfaces between the subunits and the important role of the Ctr9/Paf1 subcomplex as the scaffold for PAF1C assembly. The binding of Cdc73 to PAF1C was found to be important for yeast growth, and the extreme C-terminus of Rtf1 was shown to interact specifically with Ctr9. Disruption of the binding of either Cdc73 or Rtf1 to PAF1C significantly affected the level of histone H2B K123 monoubiquitination in vivo.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Mitchell A. Ellison, Sanchirmaa Namjilsuren, Margaret K. Shirra, Matthew S. Blacksmith, Rachel A. Schusteff, Eleanor M. Kerr, Fei Fang, Yufei Xiang, Yi Shi, Karen M. Arndt
Summary: The Paf1 complex is a transcription elongation factor that regulates transcription efficiency and impacts RNA synthesis. The subunits Cdc73 and Rtf1 of Paf1C are important for the association with RNA polymerase II on active genes.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Yinghua Cao, Yan Qin, Weidi Zhang, Wei Tian, Yanpeng Ren, Jiahao Ren, Junmeng Wang, Meng Wang, Junyi Jiang, Zhanxin Wang
Summary: The negative elongation factor (NELF) is a transcription elongation factor composed of four subunits, which plays a role in maintaining the paused state of RNA polymerase II in eukaryotes. It works together with DRB sensitivity-inducing factor (DSIF) to inhibit transcription elongation and keep Pol II in a stably paused state downstream of the promoter. The promoter-proximal pausing caused by NELF is a common mechanism for transcriptional regulation of signal-responsive genes. This study provides a high resolution crystal structure of the NELF-B/C/E ternary complex, which improves our understanding of the molecular interactions and in vivo function of NELF.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Shibin Hu, Linna Peng, Aixia Song, Yu-Xin Ji, Jingdong Cheng, Mengyun Wang, Fei Xavier Chen
Summary: Gene expression in metazoans is controlled by promoter-proximal pausing of RNA polymerase II, which can undergo productive elongation or promoter-proximal termination. Integrator-PP2A (INTAC) plays a crucial role in determining the fate of paused polymerases, but the underlying mechanisms remain unclear. Here, we establish a rapid degradation system to dissect the functions of INTAC RNA endonuclease and phosphatase modules, revealing their distinct roles in dynamic transcriptional control.
Article
Cell Biology
Ulku Uzun, Thomas Brown, Harry Fischl, Andrew Angel, Jane Mellor
Summary: Spt4 plays a role in regulating early elongation dynamics and co-transcriptional nucleosome positioning, promoting RNA polymerase II movement through gene-body nucleosomes, especially the +2 nucleosome.
Article
Biochemistry & Molecular Biology
Sujin Zheng, Kihye Shin, Wenxiong Lin, Wenfei Wang, Xuelian Yang
Summary: In this study, four HLH genes, PePRE1-4, were identified in moso bamboo plants. PePRE1/3 were highly expressed in the internode and lamina joint of bamboo seedlings. PePRE genes were expressed at higher levels in the basal segment of elongating internode. Overexpression of PePREs in Arabidopsis resulted in longer petioles and hypocotyls, and earlier flowering. PePRE1 overexpression could restore the phenotype caused by deficiency of AtPRE genes. The accumulation of PePRE1/3 proteins as punctate structures in the cytosol was disrupted by brefeldin A. These findings provide new insights into the growth mechanism of bamboo shoots and the application of PRE genes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Kristina Zumer, Kerstin C. Maier, Lucas Farnung, Martin G. Jaeger, Petra Rus, Georg Winter, Patrick Cramer
Summary: Transcription by RNA polymerase II requires elongation factors PAF, RTF1, and SPT6. Depletion of RTF1 reduces RNA Pol II velocity, while depletion of SPT6 impairs RNA Pol II progression through nucleosomes. These findings suggest distinct roles of elongation factors in regulating RNA Pol II activity.
Article
Cell Biology
Dan Zhao, Weida Liu, Ke Chen, Zihan Wu, Huirong Yang, Yanhui Xu
Summary: Human Pol I exhibits differences in structure compared to yeast Pol I, with a more closed clamp and increased DNA contacts. Disease-associated mutations are mapped to regions of Pol I involved in catalysis and complex organization. This study provides new insights into human Pol I complex organization and efficient proofreading.
Article
Multidisciplinary Sciences
Zhou Yin, Jeremy G. Bird, Jason T. Kaelber, Bryce E. Nickels, Richard H. Ebright
Summary: The article investigates the mechanism of action of Q proteins in transcription in Lambdoid bacteriophage. The results show that Q proteins form a nozzle-like structure to prevent pause and termination of RNA polymerase during transcription. Compared to previous studies, this research reveals the structural and functional differences of Q proteins in different bacteriophages.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Chenghao Guo, Yadi Zhang, Shimin Shuai, Abire Sigbessia, Shaohua Hao, Peng Xie, Xu Jiang, Zhuojuan Luo, Chengqi Lin
Summary: In this study, it was found that the regulator SPT5 undergoes phase transition during pause release and is required for gene activation. The super elongation complex (SEC) induces the transition of SPT5 into elongation droplets during early elongation. Mutations in SEC impair the phase properties of elongation droplets and transcription. These findings suggest that SEC-mediated SPT5 phase transition is essential for pause release and early elongation, and aberrant phase properties may contribute to transcription abnormalities in diseases.
Article
Multidisciplinary Sciences
Hidehisa Takahashi, Amol Ranjan, Shiyuan Chen, Hidefumi Suzuki, Mio Shibata, Tomonori Hirose, Hiroko Hirose, Kazunori Sasaki, Ryota Abe, Kai Chen, Yanfeng He, Ying Zhang, Ichigaku Takigawa, Tadasuke Tsukiyama, Masashi Watanabe, Satoshi Fujii, Midori Iida, Junichi Yamamoto, Yuki Yamaguchi, Yutaka Suzuki, Masaki Matsumoto, Keiichi Nakayama, Michael P. Washburn, Anita Saraf, Laurence Florens, Shigeo Sato, Chieri Tomomori-Sato, Ronald C. Conaway, Joan W. Conaway, Shigetsugu Hatakeyama
NATURE COMMUNICATIONS
(2020)
Article
Multidisciplinary Sciences
Shumpei Tateno, Midori Iida, Satoshi Fujii, Tetsufumi Suwa, Miki Katayama, Haruka Tokuyama, Junichi Yamamoto, Takumi Ito, Satoshi Sakamoto, Hiroshi Handa, Yuki Yamaguchi
SCIENTIFIC REPORTS
(2020)
Article
Biochemistry & Molecular Biology
Junichi Yamamoto, Tetsufumi Suwa, Yuki Murase, Shumpei Tateno, Hirotaka Mizutome, Tomoko Asatsuma-Okumura, Nobuyuki Shimizu, Tsutomu Kishi, Shuji Momose, Masahiro Kizaki, Takumi Ito, Yuki Yamaguchi, Hiroshi Handa
NATURE CHEMICAL BIOLOGY
(2020)
Article
Oncology
Mitsuhito Hirano, Yoichi Imai, Yuta Kaito, Takahiko Murayama, Kota Sato, Tadao Ishida, Junichi Yamamoto, Takumi Ito, Muneyoshi Futami, Masaki Ri, Hiroshi Yasui, Tamami Denda, Yukihisa Tanaka, Yasunori Ota, Masanori Nojima, Yasuhiko Kamikubo, Noriko Gotoh, Shinsuke Iida, Hiroshi Handa, Arinobu Tojo
Summary: The study found that the combination of HDAC inhibitor and Akt inhibitor holds promise for the treatment of relapsed/refractory MM, as HDAC inhibitors suppressed drug-resistant MM cell growth and enhanced antibody-dependent cellular cytotoxicity, while also downregulating c-Myc through GSK-3 phosphorylation blockage.
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
(2021)
Article
Oncology
Mariko Ishibashi, Junichi Yamamoto, Takumi Ito, Hiroshi Handa, Mika Sunakawa-Kii, Koiti Inokuchi, Rimpei Morita, Hideto Tamura
Summary: IMiDs induce PD-L1 expression on MM cells through the BCMA-APRIL pathway and Ikaros degradation mediated by CRBN. Combination therapy of durvalumab and IMiDs effectively reverses T-cell inhibition induced by PD-L1-upregulated cells.
MOLECULAR CANCER THERAPEUTICS
(2021)
Article
Biochemistry & Molecular Biology
Masahiko Okuda, Tetsufumi Suwa, Hidefumi Suzuki, Yuki Yamaguchi, Yoshifumi Nishimura
Summary: This study reveals that the shared N-terminal tail (NTT) of the common subunit RPB6 in all three eukaryotic RNA polymerases interacts with the PH domain (PH-D) of the p62 subunit of TFIIH, playing crucial roles in transcription and nucleotide excision repair.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biology
Nobuyuki Shimizu, Tomoko Asatsuma-Okumura, Junichi Yamamoto, Yuki Yamaguchi, Hiroshi Handa, Takumi Ito
Summary: Pomalidomide and lenalidomide, derived from thalidomide, are immunomodulatory agents with different indications. Pomalidomide has been shown to induce degradation of PLZF-RAR α, leading to anti-proliferative effects in leukemic cells.
COMMUNICATIONS BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Hidefumi Suzuki, Ryota Abe, Miho Shimada, Tomonori Hirose, Hiroko Hirose, Keisuke Noguchi, Yoko Ike, Nanami Yasui, Kazuki Furugori, Yuki Yamaguchi, Atsushi Toyoda, Yutaka Suzuki, Tatsuro Yamamoto, Noriko Saitoh, Shigeo Sato, Chieri Tomomori-Sato, Ronald C. Conaway, Joan W. Conaway, Hidehisa Takahashi
Summary: This study demonstrates the importance of Mediator in the transcription termination of replication-dependent histone genes. Mediator plays a role in pausing RNA polymerase II at the transcript end sites of these genes by associating with Cajal bodies, thereby facilitating the subsequent 3'-end processing.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Noriyuki Azuma, Tadashi Yokoi, Taku Tanaka, Emiko Matsuzaka, Yuki Saida, Sachiko Nishina, Miho Terao, Shuji Takada, Maki Fukami, Kohji Okamura, Kayoko Maehara, Tokiwa Yamasaki, Jun Hirayama, Hiroshi Nishina, Hiroshi Handa, Yuki Yamaguchi
Summary: This study reports the molecular and genetic characterization of Integrator complex subunit 15 (INTS15). INTS15 is highly expressed in the eye and brain, and it interacts with the Integrator complex to support small nuclear RNA 3' end processing. Knockdown of INTS15 leads to missplicing of numerous genes and affects genes associated with eye and brain development.
HUMAN MOLECULAR GENETICS
(2023)
Review
Chemistry, Multidisciplinary
Junichi Yamamoto, Takumi Ito, Yuki Yamaguchi, Hiroshi Handa
Summary: Progress in strategies aimed at breaking down therapeutic target proteins has led to a paradigm shift in drug discovery. Thalidomide and its derivatives are currently the only protein degraders used in clinical practice. Understanding of their molecular mechanism of action, specifically their direct target cereblon (CRBN), has advanced dramatically. This discovery has demonstrated the clinical value of thalidomide derivatives and has contributed to the rapid development of protein-degrading agents.
CHEMICAL SOCIETY REVIEWS
(2022)
Review
Biochemistry & Molecular Biology
Takumi Ito, Yuki Yamaguchi, Hiroshi Handa
Summary: CRBN, originally associated with intellectual disability, is now recognized as the primary target of thalidomide, promoting ubiquitination and proteasomal degradation of specific neosubstrates. Small-molecule drugs binding CRBN, known as molecular glue degraders, enhance the interaction between CRBN and its neosubstrates. CRBN-based PROTACs, heterobifunctional molecules hijacking CRBN to induce degradation of target proteins, show promise in drug development.
CELL CHEMICAL BIOLOGY
(2021)