Cells need to coordinate gene expression and metabolic state. Inosine monophosphate dehydrogenase (IMPDH) controls the guanine nucleotide pool and, thereby, cell proliferation. We found that Drosophila IMPDH is also a DNA-binding transcriptional repressor. IMPDH attenuates expression of histone genes and E2f, a key driver of cell proliferation. Nuclear IMPDH accumulates during the G2 phase of the cell cycle or following replicative or oxidative stress. Thus, IMPDH can couple the expression of histones and E2F to cellular state. Genome-wide profiling and in vitro binding assays established that IMPDH binds sequence specifically to single-stranded, CT-rich DNA elements. Surprisingly, this DNA-binding function is conserved in E. coli IMPDH. The catalytic function of IMPDH is not required for DNA binding. Yet substitutions that correspond to human retinitis pigmentosa mutations disrupt IMPDH binding to CT-rich, single-stranded DNA elements. By doubling as nucleotide biosynthetic enzyme or transcription factor, IMPDH can either enable or restrict cell proliferation.
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