Description: A Self-Activated Mechanism for Nucleic Acid Polymerization Catalyzed by DNA/RNA Polymerases

This title appears in the Scientific Report : 2016

A Self-Activated Mechanism for Nucleic Acid Polymerization Catalyzed by DNA/RNA Polymerases

The enzymatic polymerization of DNA and RNA is the basis for genetic inheritance for all living organisms. It is catalyzed by the DNA/RNA polymerase (Pol) superfamily. Here, bioinformatics analysis reveals that the incoming nucleotide substrate always forms an H-bond between its 3′-OH and β-phosphat...

Personal Name(s):	Genna, Vito
	Vidossich, Pietro / Ippoliti, Emiliano / Carloni, Paolo (Corresponding author) / Vivo, Marco De (Corresponding author)
Contributing Institute:	Computational Biomedicine; INM-9 Computational Biomedicine; IAS-5
Published in:	Journal of the American Chemical Society, 138 (2016) 44, S. 14592 - 14598
Imprint:	Washington, DC American Chemical Society 2016
PubMed ID:	27530537
DOI:	10.1021/jacs.6b05475
Document Type:	Journal Article
Research Program:	Addenda
Link:	OpenAccess OpenAccess
	Publikationsportal JuSER

Please use the identifier: http://dx.doi.org/10.1021/jacs.6b05475 in citations.
Please use the identifier: http://hdl.handle.net/2128/12752 in citations.

The enzymatic polymerization of DNA and RNA is the basis for genetic inheritance for all living organisms. It is catalyzed by the DNA/RNA polymerase (Pol) superfamily. Here, bioinformatics analysis reveals that the incoming nucleotide substrate always forms an H-bond between its 3′-OH and β-phosphate moieties upon formation of the Michaelis complex. This previously unrecognized H-bond implies a novel self-activated mechanism (SAM), which synergistically connects the in situ nucleophile formation with subsequent nucleotide addition and, importantly, nucleic acid translocation. Thus, SAM allows an elegant and efficient closed-loop sequence of chemical and physical steps for Pol catalysis. This is markedly different from previous mechanistic hypotheses. Our proposed mechanism is corroborated via ab initio QM/MM simulations on a specific Pol, the human DNA polymerase-η, an enzyme involved in repairing damaged DNA. The structural conservation of DNA and RNA Pols supports the possible extension of SAM to Pol enzymes from the three domains of life.