DNA mismatch repair (MMR) and very-short patch (VSP) repair are two pathways 
involved in the repair of T:G mismatches. To learn about competition and 
cooperation between these two repair pathways, we analyzed the physical and 
functional interaction between MutL and Vsr using biophysical and biochemical 
methods. Analytical ultracentrifugation reveals a nucleotide-dependent 
interaction between Vsr and the N-terminal domain of MutL. Using chemical 
crosslinking, we mapped the interaction site of MutL for Vsr to a region between 
the N-terminal domains similar to that described before for the interaction 
between MutL and the strand discrimination endonuclease MutH of the MMR system. 
Competition between MutH and Vsr for binding to MutL resulted in inhibition of 
the mismatch-provoked MutS- and MutL-dependent activation of MutH, which 
explains the mutagenic effect of Vsr overexpression. Cooperation between MMR and 
VSP repair was demonstrated by the stimulation of the Vsr endonuclease in a 
MutS-, MutL- and ATP-hydrolysis-dependent manner, in agreement with the 
enhancement of VSP repair by MutS and MutL in vivo. These data suggest a mobile 
MutS-MutL complex in MMR signalling, that leaves the DNA mismatch prior to, or 
at the time of, activation of downstream effector molecules such as Vsr or MutH.