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??