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@ARTICLE{Genna:820513,
author = {Genna, Vito and Gaspari, Roberto and Dal Peraro, Matteo
and De Vivo, Marco},
title = {{C}ooperative motion of a key positively charged residue
and metal ions for {DNA} replication catalyzed by human
{DNA} {P}olymerase-η},
journal = {Nucleic acids symposium series},
volume = {44},
number = {6},
issn = {1362-4962},
address = {Oxford},
publisher = {Oxford Univ. Press69994},
reportid = {FZJ-2016-05806},
pages = {2827 - 2836},
year = {2016},
abstract = {Trans-lesion synthesis polymerases, like DNA Polymerase-η
(Pol-η), are essential for cell survival. Pol-η 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-η 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-η
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-η 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.},
cin = {IAS-5 / INM-9},
ddc = {540},
cid = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121},
pnm = {899 - ohne Topic (POF3-899)},
pid = {G:(DE-HGF)POF3-899},
typ = {PUB:(DE-HGF)16},
UT = {WOS:000374570500036},
pubmed = {pmid:26935581},
doi = {10.1093/nar/gkw128},
url = {https://juser.fz-juelich.de/record/820513},
}