n sequence specific DNA binding activity that contributes to reinforce TDG binding to DNA at the expense of the enzymatic turnover, a partial competition between SUMO 1 and TDG RD could therefore selleck Dasatinib sufficiently destabilize the TDG DNA complex with, as a consequence, an increase of G,T U turnover. Given the relatively low affinity of TDG N for DNA, a sub stantial amount of free DNA is found within the equimolar TDG N, DNA mixture possibly leading to many unproductive SUMO 1, DNA complexes. In the context of the entire TDG, as the presence of a SBM will favor the recruit ment of SUMO 1 leading to a significant increase of its local concentration in the near vicinity of RD, the com petition between SUMO 1 and RD might be more pro nounced. We have shown that such a competitive mechanism is indeed feasible.

Discussion We have found that the posttranslational modification of TDG by SUMO 1 has no detectable effect on the conformational dynamics of the regulatory domain and rather acts on the TDG CAT and TDG C terminal conformations and stimulates both G,T and G,U glycosylase activities with a more pronounced effect Inhibitors,Modulators,Libraries on G,U substrates. Inhibitors,Modulators,Libraries It has been shown that SUMO 1 covalent attachment to TDG results in a destabilization of the TDG DNA complex Inhibitors,Modulators,Libraries leading to increased TDG turnover. It has been proposed that SUMO 1 conjugation by mimicking the effect of N terminal domain truncation on the TDG glycosylase turnover rates could induce long range conformational changes on this TDG N terminal domain. Inhibitors,Modulators,Libraries How ever, no modification of the N terminal conformation was detected on full length TDG conjugated to SUMO 1 by NMR spectroscopy.

In contrast, the SUMO 1 non covalent interaction through a unique SBM localized at the C terminal region of TDG CAT competes with the TDG regulatory domain Anacetrapib for the binding to the catalytic domain. SUMO 1 thereby is able to partially displace the regulatory domain from the RD CAT inter face leading to a primed extended conformation of TDG RD which preserves a sequence independent DNA binding activity as previously observed. Furthermore, since a modifica tion of the C terminus conformation has been observed resembling the effect of covalent SUMO 1 modification, it was possible to show that the intermole cular binding of SUMO 1 induces the same modifica tion of the TDG CAT structure.

Moreover, we have demonstrated that both N and C terminal conforma tional modifications were only induced selleck MEK162 by SUMO 1 binding to the C terminal SBM and intermolecular SUMO 1 binding still occur in the context of sumoylated TDG. Similarly to a DNA substrate containing a normal G,C pair, DNA containing a G,T U mismatch alters the RD CAT interface and stabilizes the RD extended con former. The RD in its extended conformation interacts with DNA in a sequence independent manner. Such interactions pre serve the RD DNA contacts essential for the G,T pro cessing while the RD CAT interactions contributes to decrease the G,T U turnover rates. Remarkably, SUMO 1 does not modify t