NTUIMCB

A novel mechanism of TERRA in epigenetic regulation

Epigenetic regulation is crucial for governing gene activity. This intricate process encompasses alterations in DNA modification, SNA structures, histone modification, and the involvement of non-coding RNAs. Within the genome, distinct DNA structures exist beyond the B-form, including G-quadruplexes (G4), which are stacked quinine tetrads and are involved in regulation of transcription. 

TERRA, a long non-coding RNA with telomeric repeat sequences, can fold into an RNA G-quadruplex and interact with chromatin remodeler ATRX. ATRX, a chromatin modifier with DNA G4 binding ability, has emerged as one of prevalent genes linked to human intellectual disability. Mutations in ATRX gene give rise to ATRX syndrome, characterized by cognitive impairment, facial and skeletal anomalies, and thalassemia traits. Our findings unveil that TERRA plays a role in inhibiting ATRX binding to chromatin, thereby upholding DNA G4 structures. The G-rich property of TERRA RNA appear to sequester G4 binding proteins, preventing the unwinding of DNA G4. These discoveries shed light on prospective applications of RNA therapy for modulating gene expression and addressing various human diseases. 

Alternative lengthening of Telomeres

Telomere maintenance significantly impacts aging and cancer pathways. While telomerase is recognized for its role in lengthening telomeres, certain cancers exhibited an unconventional strategy. Termed “Alternative Lengthening of Telomeres (ALT)”, this mechanism involves break-induced replication, extending telomeres—a process observed across various eukaryotes. Notably, patients with ALT-associated cancer face higher mortality rate compared to non-ALT cases. 

Our investigations reveal that TERRA involves in generating DNA:RNA hybrids at telomeres, which alongside displaced single-stranded DNA, forming R-loop structures. TERRA R-loops are enriched in cancer cells utilizing the ALT mechanism. Our research team uncovers that TERRA R-loops initiate telomere clustering and activate DNA damage response through XPF recruitment. This DNA damage response at telomeres becomes pivotal for instigating homologous recombination and facilitating telomere synthesis in ALT cancers.

學術著作

1.     Ru-Xuan Tsai, Kuo-Chen Fang, Po-Cheng Yang, Yu-Hung Hsieh, I-Tien Chiang, Yunfei Chen, Hun-Goo Lee, Jeannie T Lee, Hsueh-Ping Catherine Chu*. (2022). TERRA regulates DNA G-quadruplex formation and ATRX recruitment to chromatin. Nucleic Acids Res, 50(21), 12217-12234. doi:10.1093/nar/gkac1114

2.     Chia-Yu Guh, Hong-Jhih Shen, Liv WeiChien Chen, Pei-Chen Chiu, I-Hsin Liao, Chen-Chia Lo, Yunfei Chen, Yu-Hung Hsieh, Ting-Chia Chang, Chien-Ping Yen, Yi-Yun Chen, Tom Wei-Wu Chen, Liuh-Yow Chen, Ching-Shyi Wu, Jean-Marc Egly & Hsueh-Ping Catherine Chu*. (2022). XPF activates break-induced telomere synthesis. Nature Communications, 13(1). doi:ARTN 578110.1038/s41467-022-33428-0

3.     Hsueh-Ping Chu*, Anand Minajigi, Yunfei Chen, Robert Morris, Chia-Yu Guh, Yu-Hung Hsieh, Myriam Boukhali, Wilhelem Haas, Jeannie T Lee. iDRiP for the systematic discovery of proteins bound directly to noncoding RNA. Nature Protocols, 2021 Jun;16(7):3672-3694. *Co-corresponding author and first author.

4.     Ke-Vin Chang , Yu-Chen Chen , Wei-Ting Wu , Hong-Jhin Shen , Kuo-Chin Huang , Hsueh-Ping Chu * and Der-Sheng Han* (2020, Dec). Expression of Telomeric Repeat–Containing RNA Decreases in Sarcopenia and Increases after Exercise and Nutrition Intervention. Nutrients, 8;12(12):E3766. *Co-corresponding author.

5.     Chia-Yu Guh , Yu-Hung Hsieh , Hsueh-Ping Chu*. *Corresponding author. Functions and Properties of Nuclear lncRNAs-from Systematically Mapping the Interactomes of lncRNAs. J Biomed Sci, 27 (1), 44. 2020 Mar 17. ---Review article

6.     Xiaolei Pan, Yun Chen, Beena Bijiu, Naveed Ahmed, Joyce Kong, Marti Goldenberg, Judy Huang, Nandakumar Mohan, Stephanie Klosek, Kian Parsa, Chia-Yu Guh, Robert Lu, Hilda A Pickett, Hsueh-Ping Chu*, and Dong Zhang.FANCM suppresses DNA replication stress at ALT telomeres by disrupting TERRA R-loops. Sci Rep. 2019 Dec 13;9(1):19110. *Co-corresponding author.

7.     Chen-Yu Wang, Teddy Jegu, Hsueh-Ping Chu , Hyun Jun Oh, and Jeannie T. Lee. Wang CY, Jegu T, Chu HP, Oh HJ, Lee JT . SMCHD1 Merges Chromosome Compartments and Assists Formation of Super-Structures on the Inactive X. Cell . 2018 Jul 12;174(2):406-421.

8.     Hsueh-Ping Chu , Catherine Cifuentes-Rojas , Barry Kesner, Eric Abey, Hyun Jung Oh, Myriam Boukhali, Wilhelm Hass, and Jeannie T. Lee. TERRA RNA Antagonizes ATRX and Protects Telomeres. Cell . 2017 June 29 Volume 170, p86-101. 

[This paper was the subject of a perspective written by Roake CM, Artandi SE. Approaching TERRA Firma: Genomic Functions of Telomeric Noncoding RNA . Cell . 2017 Jun 29;170(1):8-9.] 

[This paper was the subject of a perspective written by Koch L. Non-coding RNA : A protective role for TERRA at telomeres. Nat Rev Genet . 2017 Jul 17;18(8):453. ] 

9.     Hsueh-Ping Chu , Barry Kesner, John E. Froberg, Hyun Jung Oh, Stefan F. Pinter, and Jeannie T. Lee. PAR-TERRA directs homologous sex chromosome pairing. Nature Structural & Molecular Biology . 2017 Aug;24 (8):620-631 

10.  Athanasios Zovoilis , Catherine Cifuentes-Rojas, Hsueh-Ping Chu , Alfredo J. Hernandez, and Jeannie T. Lee. Destabilization of B2 RNA by EZH2 activates the stress response. Cell . 2016 Dec 15 Volume 167, Issue 7 , p1788–1802. 

11.  Yi Liao, Hsueh-Ping Chu *, Zhixain Hu, Jason J. Merkin, Jianmin Chen, Zuguo Liu, Kurt Degenhardt, Eileen White and Alexey G. Ryazanov. Paradoxical roles of elongation factor-2 kinase in stem cell survival . * CO-FIRST AUTHOR . J Biol. Chem. 2016 July 27 ( jbc.M116.724856 ) 

12.  Hsueh-Ping Chu , Yi Liao, James S. Novak, Zhixian Hu, Jason J. Merkin, Yuriy Shymkiv, Bart P. Braeckman, Maxim V. Dorovkov, Alexandra Nguyen, Peter M, Clifford, Robert G. Nagele, David E. Harrison, Ronald E. Ellis, Alexey G. Ryazanov. Germline quality control: eEF2K stands guard to eliminate defective oocytes. Developmental Cell . 2014 Mar 10;28(5):561-72. 

13.  Martin A. Bewley, Trong K. Pham, Helen M. Marriott, Josselin Noirel, Hsueh-Ping Chu , Saw Y. Ow, Alexey, G. Ryazanov, Robert C.Read, Moira K. B. Whyte, Benny Chain, Phillip C. Wright and David H. Dockrell. Proteomic evaluation and validation of cathepsin D regulated proteins in macrophages exposed to Streptococus pneumonia. Molecular & Cellular Proteomics . 2011 Jun;10 (6)M111.008193 

14.  Grace S. Shieh, Tsai-Hung Fan, Hsueh-Ping Chu (2008). A Bayesian approach to assessing differential expression of microarray data. Journal of Statistical Computation and Simulation , Volume 78, Issue 2 February 2008, p.179 – 191 

15.  Hsu-Shui Wu, Hui-Ting Lin, Chi-Kuang Leo Wang, Yen-Feng Chiang, Hsueh-Ping Chu , Meng-Chun Hu (2007). Human CYP11A1 promoter drives Cre recombinase expression in the brain in addition to adrenals and gonads. Genesis . 2007 Feb;45(2):59-65. 

16.  Noomen Ben El Hadj, Meng-Chun Hu, Hsueh-Ping Chu , Leo Chi-Kuang Wang, and Bon-chu Chung (2006)- Phenotypic Analysis of Mice with Steroid Deficiency. Genetically Engineered Mice Handbook , Taylor&Francis. Edited by John P. Sundberg and Tsutomu Ichiki. Chapter 19, p253- 262, 2006. 

17.  Martin Heine, Catharina I. Cramm-Behrens, Athar Ansari, Hsueh-Ping Chu , Alexey G Ryazanov, Hassan Y Naim, and Ralf Jacob. Alpha-kinase 1, a new component in apical protein transport. J Biol. Chem . 2005 Jul 8;280(27):25637-43 

18.  Meng-Chun Hu, Nai-Chi Hsu, Noomen en El Hadj, Chin-I Pai, Hsueh-Ping Chu , Chi-Kuang Leo Wang, and Bon-Chu Chung, Steriod Deficiency Syndromes in Mice with Targeted Disruption of Cyp11A1. Mol Endocrinol , 2002.16(8)p.1943-1950.

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