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Insight into the sequence-specific elements leading to increased DNA bending and ligase-mediated circularization propensity by antitumor trabectedin

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Abstract

DNA curvature is the result of a combination of both intrinsic features of the double helix and external distortions introduced by the environment and the binding of proteins or drugs. The propensity of certain double-stranded DNA (dsDNA) sequences to bend is essential in crucial biological processes, such as replication and transcription, in which proteins are known to either recognize noncanonical DNA conformations or promote their formation upon DNA binding. Trabectedin (Yondelis®) is a clinically used antitumor drug which, following covalent bond formation with the 2-amino group of guanine, induces DNA curvature and enhances the circularization ratio, upon DNA ligation, of several dsDNA constructs but not others. By means of unrestrained molecular dynamics simulations using explicitly solvated all-atom models, we rationalize these experimental findings in structural terms and shed light on the crucial, albeit possibly underappreciated, role played by T4 DNA ligase in stabilizing a bent DNA conformation prior to cyclization. Taken together, our results expand our current understanding on how DNA shape modification by trabectedin may affect both the sequence-specific recognition by transcription factors to promoter sites and RNA polymerase II binding.

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Acknowledgements

A.M. gratefully acknowledges being the recipient of a predoctoral fellowship from the University of Alcalá. This work has been financially supported by the Spanish MICINN [Project PID2019-104070RB-C22] and PharmaMar S.A.U. (Colmenar Viejo, Madrid, Spain).

Funding

Financial support from the Spanish Ministerio de Economía y Competitividad (SAF2015-64629-C2-2-R) and PharmaMar S.A.U. is gratefully acknowledged.

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  1. Area of Pharmacology, Department of Biomedical Sciences and “Unidad Asociada IQM-CSIC”, School of Medicine and Health Sciences, University of Alcalá, 28805, Alcalá de Henares, Madrid, Spain

    Alberto Mills & Federico Gago

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Correspondence to Federico Gago.

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This work is dedicated to Professor Emeritus Laurence Hurley (The University of Texas at Austin) in recognition of his mentorship and inspiring scientific contributions in the field of DNA binding drugs.

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Mills, A., Gago, F. Insight into the sequence-specific elements leading to increased DNA bending and ligase-mediated circularization propensity by antitumor trabectedin. J Comput Aided Mol Des 35, 707–719 (2021). https://doi.org/10.1007/s10822-021-00396-4

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