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IRBIT is a Novel Regulator of Ribonucleotide Reductase in Higher Eukaryotes
Author(s) -
Dasso Mary,
Arnaoutov Alexei
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.884.60
Subject(s) - ribonucleotide reductase , allosteric regulation , biology , microbiology and biotechnology , regulator , dna replication , enzyme , biochemistry , dna , protein subunit , gene
Ribonucleotide reductase (RNR) is an enzyme that supplies the balanced pools of deoxynucleotide triphosphates (dNTPs) necessary for DNA replication and maintenance of genomic integrity. RNR is subject to allosteric regulatory mechanisms in all eukaryotes, as well as to control by small protein inhibitors Sml1p and Spd1p in budding and fission yeast, respectively. We have found that the metazoan protein IRBIT controls RNR activity via a novel allosteric mechanism: IRBIT forms of a complex with RNR in a dATP‐dependent manner, stabilizing dATP in the activity site of RNR, and thus inhibiting the enzyme.Formation of the RNR‐IRBIT complex is regulated through phosphorylation of IRBIT, and ablation of IRBIT expression in HeLa cells causes imbalanced dNTP pools and altered cell cycle progression. We have begun to develop model systems for examination of IRBIT function in intact organisms, and have particularly focused on analysis of the Drosophila melanogaster midgut, a well‐characterized system for tissue generation and homeostasis. Our preliminary findings suggest that these processes are misregulated in the absence of IRBIT.