Impact of N221S missense mutation in human ribonucleotide reductase small subunit b on mitochondrial DNA depletion syndrome.

The impact of N221S mutation in hRRM2B gene, which encodes the small subunit of human ribonucleotide reductase (RNR), on RNR activity and the pathogenesis of mitochondrial DNA depletion syndrome (MDDS) was investigated. Our results demonstrate that N221 mutations significantly reduce RNR activity, suggesting its role in the development of MDDS. We proposed an allosteric regulation pathway involving a chain of three phenylalanine residues on the αE helix of RNR small subunit β.

LKB1 deficiency promotes proliferation and invasion of glioblastoma through activation of mTOR and focal adhesion kinase signaling pathways.

Liver kinase B1 (LKB1), a serine/threonine kinase, is frequently inactivated in several types of human cancers. To date, inactivation of LKB1 tumor suppressor has rarely been reported in glioblastoma. In this study, we investigated LKB1 status, biological significance, and therapeutic implications in glioblastoma.

A homozygous variant in RRM2B is associated with severe metabolic acidosis and early neonatal death.

RRM2B encodes the crucial p53-inducible ribonucleotide reductase small subunit 2 homolog (p53R2), which is required for DNA synthesis throughout the cell cycle. Mutations in this gene have been associated with a lethal mitochondrial depletion syndrome. Here we present the case of an infant with a novel homozygous p.

Human mitochondrial pyrroline-5-carboxylate reductase 1 promotes invasiveness and impacts survival in breast cancers.

Human mitochondrial pyrroline-5-carboxylate reductase (PYCR) is a house-keeping enzyme that catalyzes the reduction of Δ1-pyrroline-5-carboxylate to proline. This enzymatic cycle plays pivotal roles in amino acid metabolism, intracellular redox potential and mitochondrial integrity. Here, we hypothesize that PYCR1 might be a novel prognostic biomarker and therapeutic target for breast cancer.

PYCR1 and PYCR2 Interact and Collaborate with RRM2B to Protect Cells from Overt Oxidative Stress.

Ribonucleotide reductase small subunit B (RRM2B) is a stress response protein that protects normal human fibroblasts from oxidative stress. However, the underlying mechanism that governs this function is not entirely understood. To identify factors that interact with RRM2B and mediate anti-oxidation function, large-scale purification of human Flag-tagged RRM2B complexes was performed.

Nelfinavir and nelfinavir analogs block site-2 protease cleavage to inhibit castration-resistant prostate cancer.

Nelfinavir and its analogs inhibit proliferation and induce apoptosis of castration-resistant prostate cancer through inhibition of site-2 protease (S2P) activity, which leads to suppression of regulated intramembrane proteolysis. Western blotting in nelfinavir and its analog treated cells confirms accumulation of precursor SREBP-1 and ATF6. Nelfinavir and its analogs inhibit human homolog M.

A germline missense mutation in COQ6 is associated with susceptibility to familial schwannomatosis.

Purpose: Schwannomatosis, a subtype of neurofibromatosis, is characterized by multiple benign, nonvestibular, nonintradermal schwannomas. Although the tumor suppressor SMARCB1 gene has been frequently identified as the underlying genetic cause of half of familial and ~10% of sporadic schwannomatosis, for most other cases, further causative genes remain to be discovered. Herein, we characterize the genome of a schwannomatosis family without constitutional inactivation of the SMARCB1 gene to explore novel genomic alterations predisposing individuals to the familial disease.

Ligand-independent and tissue-selective androgen receptor inhibition by pyrvinium.

Pyrvinium pamoate (PP) is a potent noncompetitive inhibitor of the androgen receptor (AR). Using a novel method of target identification, we demonstrate that AR is a direct target of PP in prostate cancer cells. We demonstrate that PP inhibits AR activity via the highly conserved DNA binding domain (DBD), the only AR inhibitor that functions via this domain.

The emerging and diverse roles of sirtuins in cancer: a clinical perspective.

Sirtuins are a highly conserved family of nicotinamide adenine dinucleotide (NAD(+))-dependent protein lysine modifying enzymes with deacetylase, adenosine diphosphateribosyltransferase and other deacylase activities. Mammals have seven sirtuins, namely SIRT1-7. They are key regulators for a wide variety of cellular and physiological processes such as cell proliferation, differentiation, DNA damage and stress response, genome stability, cell survival, metabolism, energy homeostasis, organ development, aging, and cancer.

A small-molecule blocking ribonucleotide reductase holoenzyme formation inhibits cancer cell growth and overcomes drug resistance.

Ribonucleotide reductase (RNR) is an attractive target for anticancer agents given its central function in DNA synthesis, growth, metastasis, and drug resistance of cancer cells. The current clinically established RNR inhibitors have the shortcomings of short half-life, drug resistance, and iron chelation. Here, we report the development of a novel class of effective RNR inhibitors addressing these issues.

The LRF transcription factor regulates mature B cell development and the germinal center response in mice.

B cells play a central role in immune system function. Deregulation of normal B cell maturation can lead to the development of autoimmune syndromes as well as B cell malignancies. Elucidation of the molecular features of normal B cell development is important for the development of new target therapies for autoimmune diseases and B cell malignancies.

2.6 A X-ray crystal structure of human p53R2, a p53-inducible ribonucleotide reductase .

Human p53R2 (hp53R2) is a 351-residue p53-inducible ribonucleotide reductase (RNR) small subunit. It shares >80% sequence identity with hRRM2, the small RNR subunit responsible for normal maintenance of the deoxyribonucleotide (dNTP) pool used for DNA replication, which is active during the S phase in a cell cycle-dependent fashion. But rather than cyclic dNTP synthesis, hp53R2 has been shown to supply dNTPs for DNA repair to cells in G0-G1 in a p53-dependent fashion.

A dityrosyl-diiron radical cofactor center is essential for human ribonucleotide reductases.

Ribonucleotide reductase catalyzes the reduction of ribonucleotides to deoxyribonucleotides for DNA biosynthesis. A tyrosine residue in the small subunit of class I ribonucleotide reductase harbors a stable radical, which plays a central role in the catalysis process. We have discovered that an additional tyrosine residue, conserved in human small subunits hRRM2 and p53R2, is required for the radical formation and enzyme activity.

Determination of the potency and subunit-selectivity of ribonucleotide reductase inhibitors with a recombinant-holoenzyme-based in vitro assay.

Ribonucleotide reductase (RR) is an important therapeutic target for anticancer drugs. The structure of human RR features a 1:1 complex of two homodimeric subunits, hRRM1 and hRRM2. p53R2 is a newly identified homologue of hRRM2.

Flavone and isoflavone phytoestrogens are agonists of estrogen-related receptors.

While estrogen-related receptors (ERRalpha, ERRbeta, and ERRgamma) share a high amino acid sequence homology with estrogen receptors (ERs), estrogens are not ligands of ERRs. Structure-function studies from this and other laboratories have revealed that ERRs have small ligand-binding pockets and have provided evidence to show that these receptors can activate gene transcription in a constitutive manner. To address the question as to whether there is any agonist for ERRs, our laboratory recently performed virtual ligand screening on ERRalpha that predicted flavone and isoflavone phytoestrogens to be ligands of this receptor.