Mol. Cell, published online 31 May 2012, doi:10.1016/j.molcel.2012.04.030

Credit: PETER VERRIJZER

Inosine monophosphate dehydrogenase (IMPDH) catalyzes the oxidation of IMP to xanthosine monophosphate and controls the guanine nucleotide pool and therefore DNA replication and cell proliferation. Kozhevnikova et al. show that IMPDH has an additional role: it functions as a DNA-binding transcriptional repressor. In Drosophila cells after DNA replication or under oxidative stress, the authors observed that IMPDH was localized in the nucleus and was bound to chromatin. Staining of Drosophila chromosomes, chromatin immunoprecipitation (ChIP) and IMPDH knockdown experiments revealed that, at the end of S phase of the cell cycle, IMPDH binds and represses the expression of histone genes and E2f, which encodes a transcription factor important for G1-S transition and DNA replication. A genome-wide search for IMPDH binding sites by ChIP-chip technology followed by sequence alignments showed that IMPDH recognizes CT-rich loci—specifically the consensus T(T/C)CTC. Previous studies have showed that IMPDH is composed of two domains: one catalytic domain and one cystathionine-β-synthase (CBS) subdomain. CBS is not required for IMPDH's enzymatic activity, but it has been implicated in nucleic acid binding. By mutating either the catalytic or the CBS domain, the authors showed that the enzymatic activity of IMPDH is dispensable for DNA binding, which depends on the CBS domain. This study demonstrates that, in addition its role in nucleotide biosynthesis, IMPDH can act as a transcriptional repressor after completion of DNA replication or under oxidative stress.