TY - JOUR
T1 - Asymmetric base-pair opening drives helicase unwinding dynamics
AU - Colizzi, Francesco
AU - Perez-Gonzalez, Cibran
AU - Fritzen, Remi
AU - Levy, Yaakov
AU - White, Malcolm F.
AU - Penedo, J. Carlos
AU - Bussi, Giovanni
N1 - We thank Anna Marie Pyle for enlightening suggestions and Dan Tawfik for critically reading the manuscript and inspiring discussions. Biljana Petrovic Stojanovska is acknowledged for expression and purification of PcrA and XPD and Tanya Yates at IRB Barcelona for editorial support. We are grateful to the Lafontaine laboratory, Université de Sherbrooke (UdeS), and the numerous colleagues who have shared their comments throughout the development of this work. F.C. thanks Laurène Bastet, Gaston Giroux, and the Bibliothèque Roger-Maltais at UdeS for providing infrastructures and support. F.C. acknowledges sabbatical funding (2013 to 2015) from Romano Colizzi and Maria Gaudio in Taranto, Italy, and has received support by the European Union’s Horizon 2020 Research and Innovation Programme under Marie Skłodowska-Curie Grant 752415. C.P.-G. thanks the Engineering and Physical Sciences Research Council (EPSRC) and the University of St. Andrews for financial support. Work in M.F.W. and J.C.P.’s laboratories was supported by Grant 091825/Z/10/Z from the Wellcome Trust. G.B.’s laboratory has received funding from the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC Grant 306662, S-RNA-S. Author contributions: F.C. and G.B. conceived the study; F.C., J.C.P., and G.B. designed research; F.C., C.P.-G., R.F., J.C.P., and G.B. performed research; F.C., M.F.W., J.C.P., and G.B. contributed new reagents/analytic tools; F.C., C.P.-G., R.F., Y.L., M.F.W., J.C.P., and G.B. analyzed data; C.P.-G., R.F., Y.L., and M.F.W. provided inputs for the manuscript; and F.C., J.C.P., and G.B. wrote the paper.
PY - 2019/11/5
Y1 - 2019/11/5
N2 - The opening of a Watson-Crick double helix is required for crucial cellular processes, including replication, repair, and transcription. It has long been assumed that RNA or DNA base pairs are broken by the concerted symmetric movement of complementary nucleobases. By analyzing thousands of base-pair opening and closing events from molecular simulations, here, we uncover a systematic stepwise process driven by the asymmetric flipping-out probability of paired nucleobases. We demonstrate experimentally that such asymmetry strongly biases the unwinding efficiency of DNA helicases toward substrates that bear highly dynamic nucleobases, such as pyrimidines, on the displaced strand. Duplex substrates with identical thermodynamic stability are thus shown to be more easily unwound from one side than the other, in a quantifiable and predictable manner. Our results indicate a possible layer of gene regulation coded in the direction-dependent unwindability of the double helix.
AB - The opening of a Watson-Crick double helix is required for crucial cellular processes, including replication, repair, and transcription. It has long been assumed that RNA or DNA base pairs are broken by the concerted symmetric movement of complementary nucleobases. By analyzing thousands of base-pair opening and closing events from molecular simulations, here, we uncover a systematic stepwise process driven by the asymmetric flipping-out probability of paired nucleobases. We demonstrate experimentally that such asymmetry strongly biases the unwinding efficiency of DNA helicases toward substrates that bear highly dynamic nucleobases, such as pyrimidines, on the displaced strand. Duplex substrates with identical thermodynamic stability are thus shown to be more easily unwound from one side than the other, in a quantifiable and predictable manner. Our results indicate a possible layer of gene regulation coded in the direction-dependent unwindability of the double helix.
UR - http://www.scopus.com/inward/record.url?scp=85074462526&partnerID=8YFLogxK
U2 - 10.1073/pnas.1901086116
DO - 10.1073/pnas.1901086116
M3 - مقالة
SN - 0027-8424
VL - 116
SP - 22471
EP - 22477
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 45
ER -