RRM2

Official Full Name

ribonucleotide reductase regulatory subunit M2

Organism

Homo sapiens

GeneID

6241

Background

This gene encodes one of two non-identical subunits for ribonucleotide reductase. This reductase catalyzes the formation of deoxyribonucleotides from ribonucleotides. Synthesis of the encoded protein (M2) is regulated in a cell-cycle dependent fashion. Transcription from this gene can initiate from alternative promoters, which results in two isoforms that differ in the lengths of their N-termini. Related pseudogenes have been identified on chromosomes 1 and X. [provided by RefSeq, Sep 2009]

Synonyms

R2; RR2; RR2M; C2orf48;

Bio Chemical Class

CH/CH oxidoreductase

Protein Sequence

MLSLRVPLAPITDPQQLQLSPLKGLSLVDKENTPPALSGTRVLASKTARRIFQEPTEPKTKAAAPGVEDEPLLRENPRRFVIFPIEYHDIWQMYKKAEASFWTAEEVDLSKDIQHWESLKPEERYFISHVLAFFAASDGIVNENLVERFSQEVQITEARCFYGFQIAMENIHSEMYSLLIDTYIKDPKEREFLFNAIETMPCVKKKADWALRWIGDKEATYGERVVAFAAVEGIFFSGSFASIFWLKKRGLMPGLTFSNELISRDEGLHCDFACLMFKHLVHKPSEERVREIIINAVRIEQEFLTEALPVKLIGMNCTLMKQYIEFVADRLMLELGFSKVFRVENPFDFMENISLEGKTNFFEKRVGEYQRMGVMSSPTENSFTLDADF

Open

Disease

Human immunodeficiency virus disease, Myeloproliferative neoplasm, Pancreatic cancer, Solid tumour/cancer, Stomach cancer, Unspecific body region injury

Approved Drug

2 +

Clinical Trial Drug

5 +

Discontinued Drug

2 +

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Detailed Information

The coding region of RRM2 consists of 1,170 nucleotides and encodes a protein of 389 amino acids with a theoretical molecular weight of 44,883 Da. The RRM2 subunit is composed of 13 helices and two β-sheets, including eight long helices (αA–αH) and four short helices (α1–α4). RRM2 contains a di-iron center, which is coordinated by six hydrophilic residues from four helices and two essential tyrosine residues from the C helix. A hydrogen bond network links tyrosine and the iron cluster via glutamine, representing a unique mechanism for regulating ribonucleotide reductase (RR) activity. The tyrosine residue Tyr162 is crucial for the generation and stabilization of free radicals.

Figure 1. Structures of RRM2. (Zuo Z, et al., 2019)

Expression regulation

In drug-resistant tumor cells, the RRM2 gene and its promoter region are often amplified, leading to elevated transcription. RRM2 expression is cell cycle-dependent: it is undetectable in G1 phase, peaks during S phase, and undergoes degradation after mitosis. This regulation occurs at multiple levels, including promoter elements, DNA methylation, signaling pathways, transcription factors, noncoding RNAs, protein synthesis, post-translational modifications, and protein degradation.

Dual functions of RRM2

Enzymatic function: DNA replication is a hallmark of cancer, and some chemotherapeutic agents exert antitumor effects by disrupting this process. Activation of RRM1 is associated with drug resistance in cancer cells, and overexpression of RRM2 has been identified as a potential factor contributing to resistance. In hydroxyurea-resistant KB cell lines, RRM2 gene amplification results in increased mRNA and protein levels, leading to enhanced RR activity. Inhibition of RRM2 has been shown to overcome resistance in fibrosarcoma and pancreatic cancer, thereby improving chemosensitivity. RRM2 overexpression has also been associated with resistance to hydroxyurea, tamoxifen, and doxorubicin.

Non-enzymatic function: RRM2 is implicated in ferroptosis regulation in liver cancer and is considered an iron metabolism-related gene in prostate cancer and lung adenocarcinoma. Studies suggest that RRM2 functions as an endogenous ferroptosis suppressor, as its knockout induces ferroptosis in liver and lung cancer cells. In hepatocellular carcinoma, phosphorylation of RRM2 at T33 promotes the expression of GS protein, which is essential for glutathione synthesis. Dephosphorylation of RRM2 enhances its interaction with GS, triggering proteasome-mediated degradation of both proteins. RRM2 has also been linked to tumor immunity, contributing to immune evasion. Silencing RRM2 reduces, while its overexpression increases, PD-L1 mRNA and protein levels in renal cancer cell lines such as 786-O and A498, thereby influencing responsiveness to immune checkpoint blockade therapies targeting PD-1/PD-L1.

Strategies for targeting RRM2

The RR holoenzyme plays a direct role in tumor growth and drug resistance, and RRM2 is a particularly important and promising therapeutic target since its expression is tightly regulated, while RRM1 overexpression alone does not significantly alter enzyme activity. Potential strategies to target RRM2 include disrupting its radical and iron center, chelating iron from RRM2, reducing RRM2 mRNA expression, promoting protein degradation, and developing small-molecule inhibitors directed at its active site.

Conclusion

RRM2 is a promising biomarker and therapeutic target for cancer diagnosis, treatment, and prognosis, given its critical role in DNA replication and cell proliferation. Its regulatory mechanisms are complex, involving feedback loops in which RRM2 both regulates and is regulated by multiple signaling pathways. At nearly every step from transcription to translation, RRM2 is subject to control. Although chemotherapy remains central to cancer treatment, resistance remains a major obstacle. In breast cancer, RRM2 upregulation contributes to resistance against GTI-2040, tamoxifen, doxorubicin, and cisplatin. Inhibition of RRM2 can reverse acquired resistance, but many RRM2 inhibitors have limited efficacy or adverse effects, sometimes even promoting resistance. Thus, more effective and less toxic inhibitors need to be developed. Natural products represent a potential source of anticancer agents due to their safety and low toxicity. In addition to traditional approaches with small molecules or natural products, RNA-based therapies, including lncRNA and miRNA, have emerged as new strategies. A deeper understanding of the regulatory mechanisms of RRM2 will enhance insights into tumor progression and drug resistance.

Reference

Zuo Z, Zhou Z, Chang Y, Liu Y, et al. Ribonucleotide reductase M2 (RRM2): Regulation, function, and targeting strategy in human cancer. Genes Dis. 2022 Dec 28;11(1):218-233.
Zhan Y, Jiang L, Jin X, et al. Inhibiting RRM2 to enhance the anticancer activity of chemotherapy. Biomed Pharmacother. 2021 Jan;133:110996.

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