UMO 1 conjugation, the non covalent SUMO 1 binding can act in a concentration dependent manner and would be a more flexible way to regulate TDG glycosy lase activity in a sense that it does not require the recruitment of the sumoylation and de sumoylation machinery. SUMO 1 concentra tions in a particular nuclear compartment be it free no or conjugated to another protein, could hence result in fine tuning of TDG functions, similar to mechanisms pro posed for other sumoylated or SUMO 1 binding pro teins. It has been proposed that, due to small protein protein interfaces between SUMO 1 and SBM, this interaction falls within the high micromolar range. High affinities could further result from binding to a sumoylated Inhibitors,Modulators,Libraries protein through both a SBM and a second low affinity interaction site.

Furthermore, SUMO 1 intermolecular binding could have another function like modifying the TDG inter face for its cellular partners, more particularly the RD accessibility, as already described for SUMO conjuga Inhibitors,Modulators,Libraries tion to a transcription factor not for SUMO non covalent binding. A number of studies have pointed to a central role of the RD in mediating pro tein protein interactions. A SUMO induced conformational change of the RD therefore implies a modification of the molecular interactions not only between the latter and TDGs substrates but also its interaction partners. Among them is the CREB binding protein, which could be a target of the SUMO induced RD conformational changes. Indeed, CBP is sumoylated on three lysine residues located in a region close to the HAT domain and mediates acetylation at four positions within the RD through its acetyltransferase activity.

A dual inter acting surface, SBM SUMO 1 on one hand and RD HAT on the other, leading to a high affinity complex, would involve the SUMO 1 activity of TDG not only for interaction with sumoylated Inhibitors,Modulators,Libraries CBP but in modifying the TDG RD structure in a conformation more favor able to CBP interaction and subsequent acetylation. Consistent with this, the stimulation of CBP mediated transcription by SUMO 1 binding indicates a possible role of the RD conformational dynamics in the regula tion of TDG CBP interactions. It would be now interesting to investigate at the molecular level whether the RD conformational changes we have observed with free SUMO 1 are reproducible with a sumoylated protein and whether this SUMO 1 binding activity stimulates the interaction.

Finally, a model in which sumoylation or SUMO 1 binding Inhibitors,Modulators,Libraries to TDG occurs only once TDG has per formed the glycosylase reaction and remains, GSK-3 due to the poor product dissociation rate, trapped on the aba sic G, site would also be consistent with all the experimental evidence available today. In this case sumoylation or SUMO 1 interactions selleck catalog would indeed constitute a salvage pathway removing TDG from lesions in order to allow repair to proceed. Such a mechanism might also explain why SUMO conjugating enzymes seem systematically associated with different DNA repair complexes. C