Research interest: Fidelity control of pre-mRNA splicing
Pre-mRNA splicing is an important process for eukaryotic gene expression. When it is not properly controlled, missplicing events would result in production of aberrant proteins and cause cellular dysfunctions. In recent decades, it has been shown that many diseases — cancer, autism spectrum disorders, and ß-thalassemia — are directly or indirectly caused by malfunction of pre-mRNA splicing. Therefore, in order to avoid these undesirable events, splicing fidelity has to be tightly regulated. DEAD-box RNA helicases are known not only to promote overall splicing efficiency, but also to control splicing accuracy.
Especially, Prp5, the evolutionary conserved RNA helicase, acts as a protein scaffold during an early stage of spliceosome assembly and plays a role in splicing fidelity control via its catalytic activity. During multi-step spliceosome assembly, Prp5 interacts with several splicing factors, including Hsh155, genetic mutations of which are associated with myelodysplastic syndromes (MDSs) and many types of cancers.
We have shown that the ubiquitin-like protein Hub1 binds to the DEAD-box helicase Prp5, the key regulator of early spliceosome assembly, and stimulates its ATPase activity thereby enhancing splicing and relaxing fidelity. High Hub1 levels largely enhance splicing efficiency but also come at a cost of missplicing by tolerating suboptimal splice sites and branchpoint sequences. Recently, we have shown that Hub1 is induced upon several stress, such as oxidative stress, cadmium, arsenite, and other heavy metals. Overexpression of the ubiquitin relative helps tolerance of cells to such stresses by controlling alternative splicing in yeast cells, thereby switching gene expression programs towards the stress response.
Currently, we focus on the regulation of Prp5 and Hub1 in cells to further understand their molecular mechanism in splicing fidelity control. Understanding of their function may not only contribute to the field of mRNA processing and splicing fidelity control, but also shed light on potential targets for curing missplicing-related diseases.
References:
- Chanarat, S. UBL5/Hub1: An Atypical Ubiquitin-Like Protein with a Typical Role as a Stress-Responsive Regulator. IJMS 22, 9384 (2021).
- Chanarat, S. & Svasti, J. Stress-induced upregulation of the ubiquitin-relative Hub1 modulates pre-mRNA splicing and facilitates cadmium tolerance in Saccharomyces cerevisiae. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research 1867, 118565 (2020).
- Chanarat, S. & Mishra, S. K. Emerging Roles of Ubiquitin-like Proteins in Pre-mRNA Splicing. Trends in Biochemical Sciences 43, 896–907 (2018).
- Karaduman, R.*, Chanarat, S.*, Pfander, B. & Jentsch, S. Error-Prone Splicing Controlled by the Ubiquitin Relative Hub1. Molecular Cell 67, 423-432.e4 (2017). * Co-first author
- Chanarat, S. & Sträßer, K. Splicing and beyond: The many faces of the Prp19 complex. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research 1833, 2126–2134 (2013).
- Chanarat, S., Burkert-Kautzsch, C., Meinel, D. M. & Sträßer, K. Prp19C and TREX: Interacting to promote transcription elongation and mRNA export. Transcription 3, 8–12 (2012).
- Chanarat, S., Seizl, M. & Sträßer, K. The Prp19 complex is a novel transcription elongation factor required for TREX occupancy at transcribed genes. Genes Dev 25, 1147–1158 (2011).
Current lab members
Wichuda Phothichaisri (SCBC/PhD)
Tanaporn Phetruen (SCBC/PhD, coadvised with Dr. Surang Chankhamhaengdecha)
Jirayu Nuadthaisong (SCBC/MSc)
Chanakan Techawisutthinan (SCBC/MSc)
Muthita Khongthongdam (SCBC/MSc)
Chanya Chuanchat (SCBI/BSc)
Bloem van Dam (Research assistant)
Narakorn Watphet (Research assistant)
Alumni
Supakan Panturat (SCBC/MSc, coadvised with Dr. Surang Chankhamhaengdecha)
Chonnikarn Charoenpanich (SCBI/BSc)
Sutida Chimasungkanun (BSIP, BSc)
Paphawarin Intapong (SCBM/BSc)
Punrada Bhumirestossunthorn (SCBM/BSc)
Pornpimol Kaenchan (SCBM/BSc)
Passamon Utsmanee (SCBM/BSc)
Parinthon Nearmnala (BSIP)
Apisit Naramittanakul (BSIP)
Raweewan Sangsri (Research assistant)
Iyarath Putchong (Research assistant)
Open positions
Independent Research Opportunities: If you are interested in a more in-depth research experience (such as independent study credit or completing a BSc thesis) please send <<Sittinan>> a detailed description of the kinds of research experience you hope to gain and tell him why you think Chanarat lab is the right place for you to accomplish those goals.
Lab Rotation Opportunities (SCBC322 and SCBC603): If you are interested in a short lab experience, please go through Current Lab Rotation Projects (make sure you log-in with your mahidol.edu account) and send <<Sittinan>> a detailed description of which and why you are interested in the project.
Graduate Research Opportunities: <<click here for more info>>