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Molecular Insights into the G-Quadruplex–Helicase Interactome and Its Functional Implications

Doctoral study program

Life Sciences (Faculty of Science, Masaryk University)

Research area

Nucleic acid structural biology

Supervisor

Lukáš Trantírek, Ph.D.

Consultant  

Anirban Ghosh, Ph.D.

Annotation

Protein-DNA interactions are critical in cellular processes and genetic instability-related conditions, particularly involving G-quadruplexes (G4) and their complementary C-rich sequences (i-Motif). Due to the composite viscoelastic environment in living cells, the polymorphism is highly complex, featuring dynamic conformational equilibrium between several folded and unfolded sub-populations driven by G4/i-Motif-binding proteins (Helicases, recruited proteins, transcription factors, etc.). Helicases are ubiquitous molecular motors involved in the homeostatic regulation of the folding/unfolding of these structures, thereby mediating replication, repair, transcription, and DNA damage response through protein barriers. Peptides from helicase motifs can be used to investigate atomistic details of G4-Helicase interactions and decipher structure-activity relations. The candidate will explore the folding and regulation of their rugged folding energy landscape of G-quadruplexes and i-Motifs in the presence of peptide fragments from the helicase motifs.

This project will utilize low and high-resolution orthogonal biophysical techniques (such as NMR, native mass spectrometry, and molecular dynamics) to investigate atomistic details of these interactions and conformational alterations. The results will shed light on the fundamental mechanisms of Helicase-Non-canonical nucleic acid interactions, which are essential for understanding G4/ i-Motif biology in fine-tuning gene expression and alleviating associated cellular dysfunctions. The design of peptide-based G4/i-Motif inhibitors can be used in (a) epigenetic-driven anticancer, neurological, or antiviral therapies by disrupting the overrepresentation of those forms, (b) non-invasive biomarkers to detect G4/i-Motif structures in biological samples (blood plasma) for disease diagnosis.

Recommended literature

• Tateishi-Karimata,H. and Sugimoto,N. (2021). Nucleic Acids Res., 49, 7839–7855.
• Sauer,M. and Paeschke,K. (2017). Biochem. Soc. Trans., 45, 1173–1182.
• Mendoza,O., Bourdoncle,A., Boulé,J.-B., Brosh,R.M. and Mergny,J.-L. (2016). Nucleic Acids Res., 44, 1989–2006.
• Chen,M.C., Tippana,R., Demeshkina,N.A., Murat,P., Balasubramanian,S., Myong,S. and Ferré-D'Amaré,A.R. (2018). Nature, 558, 465–469.
• Heddi,B., Cheong,V.V., Martadinata,H. and Phan,A.T. (2015). Proc. Natl. Acad. Sci., 112, 9608–9613.

Funding

GACR LA grant (GF24-10605K) (PI: Lukas Trantirek)
MUNI GAMU Junior star (MUNI/JS/1849/2024) (PI: Anirban Ghosh)

Requirements on candidates

Master's degree in Chemistry/Biochemistry/Biology/Biophysics

Keywords

G-quadruplex, I-Motif, Peptide, Nuclear Magnetic Resonance, Native Mass spectrometry

Information on the supervisor

Supervisor 1: Prof. Lukas Trantirek (senior Research group leader Non-Coding Genome) supervised > nine PhD students at Masaryk University. Current Supervisor of Michala Bučková (UCO: 474107) and  Vladimíra Zlínská (UCO: 474419) (Masaryk University, Brno) on their PhD thesis.

Consultant: Dr. Anirban Ghosh (Senior Researcher) supervised five junior researchers/ master students and published eight scientific articles with them during his previous research career in India and France. Current Supervisor of Trong Khai Nguyen (UCO: 551840) and  Melánie Drexlerová (UCO: 521018) (Masaryk University, Brno) on their Master's thesis at Masaryk University.

Relevant publications on the topic:

1. Zlinska, V. et al. (2024) Mol Ther Nucleic Acids 28;36(1):102405. (PI: Trantirek)
2. Víšková, P. et al. (2024) Nat Commun 15, 1992. (PI: Trantirek)
3. Gajarsky, M. et al. (2024) Angew Chem Int Ed Engl. 12;63(7):e202313226. (PI: Trantirek)
4. Ghosh, A. et al. (2022) Angew. Chem., Int. Ed. Engl., 61(40):e202207384.
5. Ghosh, A. et al. (2021) Chem. Rev., 122 (8), 7720-7839.
6. Ghosh, A. et al. (2021) Nucleic Acid Res. 49, 2333-45.

Project:

GACR LA grant (GF24-10605K) (PI: Lukas Trantirek), GACR EXPRO grant (GX19-26041X) (PI: Lukas Trantirek)

MUNI GAMU Junior star (MUNI/JS/1849/2024) (PI: Anirban Ghosh), H2020 Marie Skłodowska-Curie Action Postdoctoral Individual Grant (101068280) (PI: Anirban Ghosh)