544 Nucleic Acids Research, 2011, Vol. 39, No. 2 Once the enzyme nicks at the 30-side of an inosine site, it may recruit other factor(s) to allow it to use its inosine-dependent 30-exonuclease and non-speciﬁc 50-exonuclease to remove the inosine in the DNA. The inosine-dependent 30-exonuclease activity in vivo may be limited to remove the inosine lesion from the ﬁrst few nucleotide instead of extensive nucleotide degradation. The gap created by the multiple enzymatic actions can then be ﬁlled by a DNA polymerase and the resulting nick sealed by a DNA ligase. Interestingly, in the case of mismatch repair, human MutLa is found to be a latent endonuclease that can be activated in the presence of a mismatch, ATP, Mg2+ and multiple protein factors (23). This latent endonuclease activity from MutH-less species is activated when Mn2+ is used as a metal factor (23–26). Of course, it is also possible that the in vitro exonuclease activities are irrelevant to the in vivo process. In this scenario, independent nuclease(s) instead of endo V is involved in the post-inosine cleavage process. Regardless of whether the multiple nuclease activities are physiologic- ally relevant, this work reveals a series of concerted en- zymatic functions that may deﬁne the inner workings of endonuclease V. ACKNOWLEDGEMENTS We thank Dr Bernard Weiss and Dr Yoke Wah Kow at Emory University and members of the Cao laboratory for stimulating discussions. FUNDING Cooperative State Research, Education and Extension Service/US Department of Agriculture (SC-1700274, tech- nical contribution No. 5767); Department of Defense (W911NF-05-1-0335, W911NF-07-1-0141, W81XWH-10- 1-0385); National Institutes of Health (GM090141); Calhoun Honors College of Clemson University; Howard Hughes Medical Institute Undergraduate Fellowship. Funding for open access charge: Department of Defense. Conﬂict of interest statement. None declared. REFERENCES 1. Feng,H., Klutz,A.M. and Cao,W. 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