000219281 001__ 219281
000219281 005__ 20181203024243.0
000219281 0247_ $$2doi$$a10.1093/nar/gkw128
000219281 022__ $$a0305-1048
000219281 02470 $$2ISI$$a000374570500036
000219281 037__ $$aARTICLE
000219281 245__ $$aCooperative motion of a key positively charged residue and metal ions for DNA replication catalyzed by human DNA Polymerase-eta
000219281 260__ $$bOxford Univ Press$$c2016$$aOxford
000219281 269__ $$a2016
000219281 300__ $$a10
000219281 336__ $$aJournal Articles
000219281 520__ $$aTrans-lesion synthesis polymerases, like DNA Polymerase-eta (Pol-eta), are essential for cell survival. Pol-eta bypasses ultraviolet-induced DNA damages via a two-metal-ion mechanism that assures DNA strand elongation, with formation of the leaving group pyrophosphate (PPi). Recent structural and kinetics studies have shown that Pol-eta function depends on the highly flexible and conserved Arg61 and, intriguingly, on a transient third ion resolved at the catalytic site, as lately observed in other nucleic acid-processing metalloenzymes. How these conserved structural features facilitate DNA replication, however, is still poorly understood. Through extended molecular dynamics and free energy simulations, we unravel a highly cooperative and dynamic mechanism for DNA elongation and repair, which is here described by an equilibrium ensemble of structures that connect the reactants to the products in Pol-eta catalysis. We reveal that specific conformations of Arg61 help facilitate the recruitment of the incoming base and favor the proper formation of a pre-reactive complex in Pol-eta for efficient DNA editing. Also, we show that a third transient metal ion, which acts concertedly with Arg61, serves as an exit shuttle for the leaving PPi. Finally, we discuss how this effective and cooperative mechanism for DNA repair may be shared by other DNA-repairing polymerases.
000219281 700__ $$uIst Italiano Tecnol, Lab Mol Modeling & Drug Discovery, Via Morego 30, I-16163 Genoa, Italy$$aGenna, Vito
000219281 700__ $$uIst Italiano Tecnol, CONCEPT Lab, Via Morego 30, I-16163 Genoa, Italy$$aGaspari, Roberto
000219281 700__ $$0243887$$g182443$$uEcole Polytech Fed Lausanne, Sch Life Sci, Inst Bioengn, CH-1015 Lausanne, Switzerland$$aDal Peraro, Matteo
000219281 700__ $$uIst Italiano Tecnol, Lab Mol Modeling & Drug Discovery, Via Morego 30, I-16163 Genoa, Italy$$aDe Vivo, Marco
000219281 773__ $$j44$$tNucleic Acids Research$$k6$$q2827-2836
000219281 909C0 $$xU11830$$0252070$$pUPDALPE
000219281 909CO $$pSV$$particle$$ooai:infoscience.tind.io:219281
000219281 917Z8 $$x182443
000219281 937__ $$aEPFL-ARTICLE-219281
000219281 973__ $$rREVIEWED$$sPUBLISHED$$aEPFL
000219281 980__ $$aARTICLE