RRM2B

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Yun Yen - One of the best experts on this subject based on the ideXlab platform.

  • the single nucleotide variant at c 662a g in human RRM2B is a loss of function mutation
    Molecular Genetics & Genomic Medicine, 2020
    Co-Authors: Yentzu Tseng, Yun Yen, Weichun Huangfu, Ihsuan Liu
    Abstract:

    Background Mitochondrial DNA maintenance defects (MDMDs) is one of the critical pediatric dysfunction. One of the recent report indicated that a severe patient of MDMDs carries the NP_056528.2:p.Asn221Ser (N221S) variation in the RRM2B gene (NM_015713.5). However, there is no direct evidence demonstrating the nature of the N221S variation. Materials and methods This study aimed to utilize zebrafish and morpholino oligomer (MO) knockdown technique to provide direct evidence for the nature of the N221S variation in the RRM2B. Results The results showed that two distinct MOs were both able to perturb the expression of RRM2B in zebrafish and dose-dependently induced morphological defects. Furthermore, co-injection of human wild-type RRM2B mRNA with MO-e4i4 successfully rescued the developmental defects, whereas co-injection of RRM2B/N221S mRNA with MO-e4i4 did not rescue the developmental defects. Conclusion In conclusion, the functional assay in this study provided the direct evidence proving that the N221S variation is a loss-of-function mutation and plausibly related to the pathogenic developmental defects found in the infants of previous clinical reports.

  • RRM2B deletion causes mitochondrial metabolic defects in renal tubules
    Scientific Reports, 2019
    Co-Authors: Yifan Chen, Wei Jia, Ihsuan Lin, Yuru Guo, Weijun Chiu, Yun Yen
    Abstract:

    Renal diseases impose considerable health and economic burdens on health systems worldwide, and there is a lack of efficient methods for the prevention and treatment due to their complexity and heterogeneity. Kidneys are organs with a high demand for energy produced by mitochondria, in which RRM2B has critical functions as reported. The RRM2B kidney-specific knockout mice we generated exhibited age-dependent exacerbated features, including mitochondrial dysfunction and increased oxidative stress; additionally, resulted in severe disruption of mitochondria-related metabolism. RRM2B is vital not only to supply dNTPs for DNA replication and repair, but also to maintain structural integrity and metabolic homeostasis in mitochondria. Thence, RRM2B deletion might induce chronic kidney defects in mice. This model can facilitate exploration of novel mechanisms and targeted therapies in the kidney diseases and has important translational and clinical implications.

  • pycr1 and pycr2 interact and collaborate with RRM2B to protect cells from overt oxidative stress
    Scientific Reports, 2016
    Co-Authors: Meiling Kuo, Mabel Biner Lee, Michelle Tang, Willem Den Besten, Michael J Sweredoski, Sonja Hess, Chih Ming Chou, Chun A Changou, Wei Jia, Yun Yen
    Abstract:

    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. Pyrroline-5-carboxylate reductase 1 and 2 (PYCR1, PYCR2) were identified by mass spectrometry analysis as components of RRM2B complexes. Silencing of both PYCR1 and PYCR2 by expressing short hairpin RNAs induced defects in cell proliferation, partial fragmentation of the mitochondrial network, and hypersensitivity to oxidative stress in hTERT-immortalized human foreskin fibroblasts (HFF-hTERT). Moderate overexpression of RRM2B, comparable to stress-induced level, protected cells from oxidative stress. Silencing of both PYCR1 and PYCR2 completely abolished anti-oxidation activity of RRM2B, demonstrating a functional collaboration of these metabolic enzymes in response to oxidative stress.

  • RRM2B mediated regulation of mitochondrial activity and inflammation under oxidative stress
    Mediators of Inflammation, 2015
    Co-Authors: Er Chieh Cho, Yun-ru Liu, Meiling Kuo, Yi Chen Hsieh, Jia Hui Cheng, Yu Chi Cheng, Rong Hong Hsieh, Yun Yen
    Abstract:

    RRM2B is a critical ribonucleotide reductase (RR) subunit that exists as p53-inducible and p53-dependent molecule. The p53-independent regulation of RRM2B has been recently studied, and FOXO3 was identified as a novel regulator of RRM2B. However, the p53-independent regulation of RRM2B, particularly under oxidative stress, remains largely unknown. In this study, we investigated the role of RRM2B underoxidative stress-induced DNA damage and further examined the regulation of mitochondrial and inflammatory genes by RRM2B. Our study is the first to report the critical role of RRM2B in mitochondrial homeostasis and the inflammation signaling pathway in a p53-independent manner. Furthermore, our study provides novel insights into the role of the RR in inflammatory diseases.

  • tumor suppressor foxo3 regulates ribonucleotide reductase subunit RRM2B and impacts on survival of cancer patients
    Oncotarget, 2014
    Co-Authors: Er Chieh Cho, Meiling Kuo, Xiyong Liu, Lixin Yang, Yi Chen Hsieh, Jinghan Wang, Yawen Cheng, Yun Yen
    Abstract:

    The role of Ribonucleotide reductase (RR) subunits in different cancers has been intensively studied in our laboratory. RRM2B was identified as a p53-inducible RR subunit that involves in various critical cellular mechanisms such as cell cycle regulation, DNA repair and replication, and mitochondrial homeostasis, etc. However, little is known about the p53-independent regulation of RRM2B in cancer pathology. In this study, we discovered tumor suppressor FOXO3 as the novel regulator of RRM2B. FOXO3 directly bound to and transcriptionally activated the promoter of RRM2B, and induced the expression of RRM2B at RNA and protein levels. Moreover, Overexpression of RRM2B and/or FOXO3 inhibited the proliferation of cancer cells. The cancer tissue microarray data also demonstrated a strong correlation between the co-expression of FOXO3 plus RRM2B and increased disease survival and reduced recurrence or metastasis in lung cancer patients. Our results suggest a novel regulatory control of RRM2B function, and imply the importance of FOXO signaling pathway in DNA replication modulation. This study provides the first time evidence that RRM2B is transcriptionally and functionally regulated independent of p53 pathway by FOXO3, and it establishes that FOXO3 and RRM2B could be used as predictive biomarkers for cancer progression.

Hirofumi Arakawa - One of the best experts on this subject based on the ideXlab platform.

  • Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion.
    Nature genetics, 2007
    Co-Authors: Alice Bourdon, Limor Minai, Valérie Serre, Jean-philippe Jais, Emmanuelle Sarzi, Sophie Aubert, Dominique Chretien, Véronique Paquis-flucklinger, Hirofumi Arakawa
    Abstract:

    Mutation of RRM2B , encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion

  • impaired function of p53r2 in RRM2B null mice causes severe renal failure through attenuation of dntp pools
    Nature Genetics, 2003
    Co-Authors: Takashi Kimura, Satoshi Takeda, Yoji Sagiya, Mitsukazu Gotoh, Yusuke Nakamura, Hirofumi Arakawa
    Abstract:

    p53R2, which is regulated by tumor suppressor p53, is a small subunit of ribonucleotide reductase. To determine whether it is involved in DNA repair by supplying deoxyribonucleotides (dNTPs) for resting cells in vivo, we generated a strain of mice lacking RRM2B (encoding p53R2). These mice developed normally until they were weaned but from then on had growth retardation and early mortality. Pathological examination indicated that multiple organs had failed, and all RRM2B-null mice died from severe renal failure by the age of 14 weeks. TUNEL staining showed a greater number of apoptotic cells in kidneys of 8-week-old RRM2B-/- mice relative to wild-type mice. p53 was activated in kidney tissues of RRM2B-/- mice, leading to transcriptional induction of p53 target genes. RRM2B-/- mouse embryonic fibroblasts (MEFs) became immortal much earlier than RRM2B+/+ MEFs. dNTP pools were severely attenuated in RRM2B-/- MEFs under oxidative stress. RRM2B deficiency caused higher rates of spontaneous mutation in the kidneys of RRM2B-/- mice. Our results suggest that p53R2 has a pivotal role in maintaining dNTP levels for repair of DNA in resting cells. Impairment of this pathway may enhance spontaneous mutation frequency and activate p53-dependent apoptotic pathway(s) in vivo, causing severe renal failure, growth retardation and early mortality.

Emmanuelle Sarzi - One of the best experts on this subject based on the ideXlab platform.

  • Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion
    Nature Genetics, 2007
    Co-Authors: Alice Bourdon, Limor Minai, Valérie Serre, Jean-philippe Jais, Emmanuelle Sarzi, Sophie Aubert, Véronique Paquis-flucklinger, P. De Lonlay, Dominique Chrétien, Hirofumi Arakawa
    Abstract:

    Mitochondrial DNA (mtDNA) depletion syndrome (MDS; MIM 251880) is a prevalent cause of oxidative phosphorylation disorders characterized by a reduction in mtDNA copy number. The hitherto recognized disease mechanisms alter either mtDNA replication ( POLG (ref. 1 )) or the salvage pathway of mitochondrial deoxyribonucleosides 5′-triphosphates (dNTPs) for mtDNA synthesis ( DGUOK (ref. 2 ), TK2 (ref. 3 ) and SUCLA2 (ref. 4 )). A last gene, MPV17 (ref. 5 ), has no known function. Yet the majority of cases remain unexplained. Studying seven cases of profound mtDNA depletion (1–2% residual mtDNA in muscle) in four unrelated families, we have found nonsense, missense and splice-site mutations and in-frame deletions of the RRM2B gene, encoding the cytosolic p53-inducible ribonucleotide reductase small subunit. Accordingly, severe mtDNA depletion was found in various tissues of the RRM2B ^−/− mouse. The mtDNA depletion triggered by p53R2 alterations in both human and mouse implies that p53R2 has a crucial role in dNTP supply for mtDNA synthesis.

  • Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion.
    Nature genetics, 2007
    Co-Authors: Alice Bourdon, Limor Minai, Valérie Serre, Jean-philippe Jais, Emmanuelle Sarzi, Sophie Aubert, Dominique Chretien, Véronique Paquis-flucklinger, Hirofumi Arakawa
    Abstract:

    Mutation of RRM2B , encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion

Véronique Paquis-flucklinger - One of the best experts on this subject based on the ideXlab platform.

  • Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion
    Nature Genetics, 2007
    Co-Authors: Alice Bourdon, Limor Minai, Valérie Serre, Jean-philippe Jais, Emmanuelle Sarzi, Sophie Aubert, Véronique Paquis-flucklinger, P. De Lonlay, Dominique Chrétien, Hirofumi Arakawa
    Abstract:

    Mitochondrial DNA (mtDNA) depletion syndrome (MDS; MIM 251880) is a prevalent cause of oxidative phosphorylation disorders characterized by a reduction in mtDNA copy number. The hitherto recognized disease mechanisms alter either mtDNA replication ( POLG (ref. 1 )) or the salvage pathway of mitochondrial deoxyribonucleosides 5′-triphosphates (dNTPs) for mtDNA synthesis ( DGUOK (ref. 2 ), TK2 (ref. 3 ) and SUCLA2 (ref. 4 )). A last gene, MPV17 (ref. 5 ), has no known function. Yet the majority of cases remain unexplained. Studying seven cases of profound mtDNA depletion (1–2% residual mtDNA in muscle) in four unrelated families, we have found nonsense, missense and splice-site mutations and in-frame deletions of the RRM2B gene, encoding the cytosolic p53-inducible ribonucleotide reductase small subunit. Accordingly, severe mtDNA depletion was found in various tissues of the RRM2B ^−/− mouse. The mtDNA depletion triggered by p53R2 alterations in both human and mouse implies that p53R2 has a crucial role in dNTP supply for mtDNA synthesis.

  • Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion.
    Nature genetics, 2007
    Co-Authors: Alice Bourdon, Limor Minai, Valérie Serre, Jean-philippe Jais, Emmanuelle Sarzi, Sophie Aubert, Dominique Chretien, Véronique Paquis-flucklinger, Hirofumi Arakawa
    Abstract:

    Mutation of RRM2B , encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion

Sophie Aubert - One of the best experts on this subject based on the ideXlab platform.

  • Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion
    Nature Genetics, 2007
    Co-Authors: Alice Bourdon, Limor Minai, Valérie Serre, Jean-philippe Jais, Emmanuelle Sarzi, Sophie Aubert, Véronique Paquis-flucklinger, P. De Lonlay, Dominique Chrétien, Hirofumi Arakawa
    Abstract:

    Mitochondrial DNA (mtDNA) depletion syndrome (MDS; MIM 251880) is a prevalent cause of oxidative phosphorylation disorders characterized by a reduction in mtDNA copy number. The hitherto recognized disease mechanisms alter either mtDNA replication ( POLG (ref. 1 )) or the salvage pathway of mitochondrial deoxyribonucleosides 5′-triphosphates (dNTPs) for mtDNA synthesis ( DGUOK (ref. 2 ), TK2 (ref. 3 ) and SUCLA2 (ref. 4 )). A last gene, MPV17 (ref. 5 ), has no known function. Yet the majority of cases remain unexplained. Studying seven cases of profound mtDNA depletion (1–2% residual mtDNA in muscle) in four unrelated families, we have found nonsense, missense and splice-site mutations and in-frame deletions of the RRM2B gene, encoding the cytosolic p53-inducible ribonucleotide reductase small subunit. Accordingly, severe mtDNA depletion was found in various tissues of the RRM2B ^−/− mouse. The mtDNA depletion triggered by p53R2 alterations in both human and mouse implies that p53R2 has a crucial role in dNTP supply for mtDNA synthesis.

  • Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion.
    Nature genetics, 2007
    Co-Authors: Alice Bourdon, Limor Minai, Valérie Serre, Jean-philippe Jais, Emmanuelle Sarzi, Sophie Aubert, Dominique Chretien, Véronique Paquis-flucklinger, Hirofumi Arakawa
    Abstract:

    Mutation of RRM2B , encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion

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