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Mismatch Repair Processing of Iododeoxyuridine

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

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Mismatch Repair Processing of Iododeoxyuridine

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  1. Mismatch Repair Processing of Iododeoxyuridine Lets take an integrative approach !

  2. 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

  3. Different levels of modelling Stefan BornholdtScience 21 October 2005:Vol.310.no. 5747

  4. 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

  5. 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

  6. IUdR causes less cytotoxicity than 6-Thioguanine SE Berry et.al. Cancer Res. 1999

  7. IUdR incorporation level is associated with MLH1 function SE Berry et.al. Cancer Res. 1999

  8. MMR status and effect of IUdR as a radiosensitizer Berry, S. E. et al. Cancer Res 1999;59:1840-1845

  9. MMRBER

  10. Interaction between MED1 and MLH1 Bellacosa, Alfonso et al. PNAS (1999)

  11. MMR protein levels are reduced in Med1-deficient cells by post-transcriptional mechanism Cortellino, Salvatore et al. PNAS (2003)

  12. The two repair processes (BER and MMR) are competing or complementing while processing IUdR generated mispairs?? Is there a probable involvement of other DNA repair mechanism (s)?? What will be the consequence of the mutation of pathway gene(s) on the overall repair efficiency?? Is it possible to identify specific drug targets to achieve therapeutic gain ??

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