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 Bornholdt Science 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:

9. MMR BER

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

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

12. Is there a probable involvement of other DNA repair mechanism (s)??
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 ??