Transcript Mismatch Repair Processing of Iododeoxyuridine: Lets take an
Mismatch Repair Processing of Iododeoxyuridine Lets take an integrative approach ! Why integrative approach? • To link Mismatch repair mechanism with Base Excision Repair, as operative on IUdR mispairs • To analyze the contribution of MMR in the overall repair process • To predict the outcome of IUdR treatment in MMR proficient and deficient cells Different levels of modelling Stefan Bornholdt Science 21 October 2005:Vol.310.no. 5747 Processing of IUdR by MMR • IUdR can specifically target MMR deficient human tumor cells for radiosensitization • Radiosensitization is probably due to the formation of reactive uracilyl radicals after irradiation • MutSα(MSH2/MSH6) repair activity is correlated to its binding affinity MMR recognizes IUdR:G mispairs, better than G:T *MutSα does not bind to IUdR in a ssDNA SE Berry et.al. Cancer Res.2003 IUdR causes less cytotoxicity than 6-Thioguanine SE Berry et.al. Cancer Res. 1999 IUdR incorporation level is associated with MLH1 function SE Berry et.al. Cancer Res. 1999 MMR status and effect of IUdR as a radiosensitizer Berry, S. E. et al. Cancer Res 1999;59:1840-1845 MMR BER Interaction between MED1 and MLH1 Bellacosa, Alfonso et al. PNAS (1999) MMR protein levels are reduced in Med1deficient cells by post-transcriptional mechanism Cortellino, Salvatore et al. PNAS (2003) The two repair processes (BER and MMR) are competing or complementing while processing IUdR generated mispairs?? MMR Is it possible to identify specific drug targets to achieve therapeutic gain ?? Is there a probable involvement of other DNA repair mechanism (s)?? BER What will be the consequence of the mutation of pathway gene(s) on the overall repair efficiency??