Ribonucleotide reductase small subunit M2 (RRM2) (RRM2)

Ribonucleotide reductase small subunit M2 (RRM2) is a critical component of the Class I ribonucleotide reductase (RNR) enzyme complex, responsible for the rate-limiting step in de novo deoxyribonucleotide (dNTP) synthesis (UniProt P08571). The RRM2 subunit contains a unique di-iron center that generates and stabilizes a tyrosyl radical, which is essential for the catalytic reduction of ribonucleoside diphosphates into deoxyribonucleoside diphosphates (PubMed: 21854206). This process provides the necessary building blocks for DNA replication and repair, making RRM2 expression highly dependent on the cell cycle, with peak levels occurring during the S-phase. In many cancers, RRM2 is overexpressed, contributing to increased genomic instability and tumor progression (PubMed: 28631134). Therapeutic strategies targeting the RRM2 tyrosyl radical site typically involve radical scavengers like hydroxyurea or iron chelators like triapine, which disrupt the radical's stability and effectively inhibit DNA synthesis in malignant cells (DrugBank DB00672). By halting the production of dNTPs, these agents induce replication stress and apoptosis, particularly in rapidly dividing cells.

Other names

Ribonucleoside-diphosphate reductase subunit M2R2 subunitRibonucleotide reductase M2 polypeptideRRM2RR2

The mechanism of action involves the direct quenching of the stable tyrosyl radical (Tyr122 in humans) or the chelation of the essential di-iron center, which prevents the initiation of the catalytic cycle required for converting ribonucleotides into deoxyribonucleotides (PubMed: 21854206).