Abstract
Retinitis pigmentosa (RP) is one of the leading causes of retinal degeneration worldwide. Many inherited forms exist, and treatment is limited due to a lack of understanding of the mechanism of the disease. Mutations in the RP10 gene cause the autosomal dominant form of RP. The RP10 gene encodes 5’-inosine monophosphate dehydrogenase type 1 (hIMPDH1), which catalyzes the rate limiting step in de novo guanine nucleotide synthesis. Recently, it was discovered that IMPDH is recruited to actively transcribing genes in Saccharomyces cerevisiae. In this study, chromatin immunoprecipitation experiments in Drosophila melanogaster reveal that IMPDH is enriched at the Actin5C and MtnA promoters, both transcribed by RNA polymerase II, but not at the Ribosomal 28S promoter, which is transcribed by RNA polymerase III. As transcriptional activity of MtnA in induced, IMPDH recruitment to that gene increases two-fold. In addition, NAD(H) do not appear to affect the affinity of IMPDH for nucleic acids. Finally, RP-causing mutants of IMPDH were transfected into HEK293T cells and found to localize to the chromatin. These studies propose a new role for IMPDH in transcription. Since perturbations in transcription of certain genes in photoreceptor cells are known to cause apoptosis, these observations suggest a mechanism for IMPDH-linked hereditary blindness.";"Retinitis pigmentosa (RP) is one of the leading causes of retinal degeneration worldwide. Many inherited forms exist, and treatment is limited due to a lack of understanding of the mechanism of the disease. Mutations in the RP10 gene cause the autosomal dominant form of RP. The RP10 gene encodes 5’-inosine monophosphate dehydrogenase type 1 (hIMPDH1), which catalyzes the rate limiting step in de novo guanine nucleotide synthesis. Recently, it was discovered that IMPDH is recruited to actively transcribing genes in Saccharomyces cerevisiae. In this study, chromatin immunoprecipitation experiments in Drosophila melanogaster reveal that IMPDH is enriched at the Actin5C and MtnA promoters, both transcribed by RNA polymerase II, but not at the Ribosomal 28S promoter, which is transcribed by RNA polymerase III. As transcriptional activity of MtnA in induced, IMPDH recruitment to that gene increases two-fold. In addition, NAD(H) do not appear to affect the affinity of IMPDH for nucleic acids. Finally, RP-causing mutants of IMPDH were transfected into HEK293T cells and found to localize to the chromatin. These studies propose a new role for IMPDH in transcription. Since perturbations in transcription of certain genes in photoreceptor cells are known to cause apoptosis, these observations suggest a mechanism for IMPDH-linked hereditary blindness.