共查询到20条相似文献,搜索用时 15 毫秒
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Yalemi Morales Damon V. Nitzel Owen M. Price Shanying Gui Jun Li Jun Qu Joan M. Hevel 《The Journal of biological chemistry》2015,290(24):14915-14926
Elevated levels of asymmetric dimethylarginine (ADMA) correlate with risk factors for cardiovascular disease. ADMA is generated by the catabolism of proteins methylated on arginine residues by protein arginine methyltransferases (PRMTs) and is degraded by dimethylarginine dimethylaminohydrolase. Reports have shown that dimethylarginine dimethylaminohydrolase activity is down-regulated and PRMT1 protein expression is up-regulated under oxidative stress conditions, leading many to conclude that ADMA accumulation occurs via increased synthesis by PRMTs and decreased degradation. However, we now report that the methyltransferase activity of PRMT1, the major PRMT isoform in humans, is impaired under oxidative conditions. Oxidized PRMT1 displays decreased activity, which can be rescued by reduction. This oxidation event involves one or more cysteine residues that become oxidized to sulfenic acid (-SOH). We demonstrate a hydrogen peroxide concentration-dependent inhibition of PRMT1 activity that is readily reversed under physiological H2O2 concentrations. Our results challenge the unilateral view that increased PRMT1 expression necessarily results in increased ADMA synthesis and demonstrate that enzymatic activity can be regulated in a redox-sensitive manner. 相似文献
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《Cell reports》2020,30(12):4165-4178.e7
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J. Suchánková S. Legartová P. Sehnalová S. Kozubek S. Valente D. Labella A. Mai C. Eckerich F.O. Fackelmayer D.V. Sorokin E. Bártová 《European journal of histochemistry : EJH》2014,58(2)
Protein arginine methyltransferases (PRMTs) are responsible for symmetric and asymmetric methylation of arginine residues of nuclear and cytoplasmic proteins. In the nucleus, PRMTs belong to important chromatin modifying enzymes of immense functional significance that affect gene expression, splicing and DNA repair. By time-lapse microscopy we have studied the sub-cellular localization and kinetics of PRMT1 after inhibition of PRMT1 and after irradiation. Both transiently expressed and endogenous PRMT1 accumulated in cytoplasmic bodies that were located in the proximity of the cell nucleus. The shape and number of these bodies were stable in untreated cells. However, when cell nuclei were microirradiated by UV-A, the mobility of PRMT1 cytoplasmic bodies increased their, size was reduced, and they disappeared within approximately 20 min. The same response occurred after γ-irradiation of the whole cell population, but with delayed kinetics. Treatment with PRMT1 inhibitors induced disintegration of these PRMT1 cytoplasmic bodies and prevented formation of 53BP1 nuclear bodies (NBs) that play a role during DNA damage repair. The formation of 53BP1 NBs was not influenced by PRMT1 over-expression. Taken together, we show that PRMT1 concentrates in cytoplasmic bodies, which respond to DNA injury in the cell nucleus, and to treatment with various PRMT1 inhibitors. 相似文献
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Tingdong Tang Bin Zheng Sheng-hong Chen Anne N. Murphy Krystyna Kudlicka Huilin Zhou Marilyn G. Farquhar 《The Journal of biological chemistry》2009,284(8):5414-5424
Mitochondria are dynamic organelles that play key roles in metabolism,
energy production, and apoptosis. Coordination of these processes is essential
to maintain normal cellular functions. Here we characterized hNOA1, the human
homologue of AtNOA1 (Arabidopsis thaliana nitric oxide-associated
protein 1), a large mitochondrial GTPase. By immunofluorescence,
immunoelectron microscopy, and mitochondrial subfractionation, endogenous
hNOA1 is localized within mitochondria where it is peripherally associated
with the inner mitochondrial membrane facing the mitochondrial matrix.
Overexpression and knockdown of hNOA1 led to changes in mitochondrial shape
implying effects on mitochondrial dynamics. To identify the interaction
partners of hNOA1 and to further understand its cellular functions, we
performed immunoprecipitation-mass spectrometry analysis of endogenous hNOA1
from enriched mitochondrial fractions and found that hNOA1 interacts with both
Complex I of the electron transport chain and DAP3
(death-associated protein 3), a positive
regulator of apoptosis. Knockdown of hNOA1 reduces mitochondrial O2
consumption ∼20% in a Complex I-dependent manner, supporting a functional
link between hNOA1 and Complex I. Moreover, knockdown of hNOA1 renders cells
more resistant to apoptotic stimuli such as γ-interferon and
staurosporine, supporting a role for hNOA1 in regulating apoptosis. Thus,
based on its interactions with both Complex I and DAP3, hNOA1 may play a role
in mitochondrial respiration and apoptosis.Emerging evidence indicates that mitochondrial metabolism, apoptosis, and
dynamics (fission and fusion) are closely intertwined. Apoptosis and changes
in metabolism are associated with morphological changes in mitochondria
(1,
2). Conversely, when
mitochondrial morphology is altered either by mutations or altered expression
of mitochondrial fission or fusion proteins such as the dynamin like large G
proteins Drp1 and Opa1, the cell''s susceptibility to apoptotic agents
(3) or ability to generate ATP
(4,
5) is altered.Apoptosis is controlled by a diverse range of cell signals, which may
originate either extracellularly (extrinsic inducers) or intracellularly
(intrinsic inducers), and mitochondria play central roles in both pathways
(6). The apoptotic pathways
involve a growing list of mitochondria-associated proteins, such as Bad,
cytochrome c, Smac, AIF, Bcl-2, and others, most of which are located
either on the outer mitochondrial membrane
(OMM)3 or in the
intermembrane space (IMS) (7).
Recently, proteins of the mitochondrial matrix such as DAP3, have also been
shown to be involved in apoptosis
(8). DAP3 has been reported to
be involved in both γ-interferon-
(9) and tumor necrosis
factor-α-induced (10)
apoptosis as well as staurosporine-induced mitochondrial fragmentation
(11), but the detailed
mechanisms involved remain to be elucidated.Besides their role in apoptosis, much more is known about the functions of
mitochondria in respiration and generation of ATP. The electron transport
chain in the inner mitochondrial membrane (IMM) contains four major enzyme
complexes (Complexes I, II, III, and IV) that are involved in transferring
electrons from NADH (Complex I-linked) or FADH2 (Complex II-linked) to
O2 and in pumping protons out of the matrix to create an
electrochemical proton gradient, which is harnessed by ATP synthase to make
ATP (12).Despite the accumulating evidence showing intercommunication between
mitochondrial metabolism, apoptosis, and dynamics, how these processes are
coordinated remains to be elucidated. In this study we characterize hNOA1, the
human homologue of Arabidopsis thaliana nitric oxide-associated
protein, 1 (AtNOA1) (13).
hNOA1 is a large G protein closely related to dynamin that is associated with
the IMM. Perturbation of hNOA1 affects mitochondrial morphology, Complex
I-linked O2 consumption, and the cell''s susceptibility to apoptotic
stimuli, possibly through interactions with proteins such as Complex I and
DAP3. 相似文献
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The GAR Motif of 53BP1 is Arginine Methylated by PRMT1 and is Necessary for 53BP1 DNA Binding Activity 总被引:1,自引:0,他引:1
《Cell cycle (Georgetown, Tex.)》2013,12(12):1834-1841
The p53-binding protein 1 (53BP1) is rapidly recruited to sites of DNA double-strand breaks and forms characteristics nuclear foci, demonstrating its role in the early events of detection, signaling and repair of damaged DNA. 53BP1 contains a glycine arginine rich (GAR) motif of unknown function within its kinetochore binding domain. Herein, we show that the GAR motif of 53BP1 is arginine methylated by protein arginine methyltransferase 1 (PRMT1), the same methyltransferase that methylates MRE11. 53BP1 contains asymmetric dimethylarginines (aDMA) within cells, as detected with methylarginine-specific antibodies. Amino acid substitution of the arginines within the GAR motif of 53BP1 abrogated binding to single and double-stranded DNA, demonstrating that the GAR motif is required for DNA binding activity of 53BP1. Fibroblast cells treated with methylase inhibitors failed to relocalize 53BP1 to sites of DNA damage and formed few ?-H2AX foci, consistent with our previous data that MRE11 fails to relocalize to DNA damage sites in cells treated with methylase inhibitors. Our findings identify the GAR motif as a region required for 53BP1 DNA binding activity and is the site of methylation by PRMT1. 相似文献
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Xin Zhang Kexin Wang Xingbo Feng Jian Wang Yali Chu Chunmeng Jia Qingsi He Cheng Chen 《Cell death & disease》2021,12(11)
Abnormal angiogenesis occurs during the growth of solid tumors resulting in increased vascular permeability to fluids and metastatic cancer cells. Anti-angiogenesis therapy for solid tumors is effective in the treatment of cancer patients. However, the efficacy of anti-angiogenesis therapy is limited by drug resistance. The findings of the current study showed that HIF1α R282 is methylated by PRMT3, which is necessary for its stabilization and oncogene function. Analysis showed that PRMT3-mediated tumorigenesis is HIF1α methylation-dependent. A novel therapeutic molecule (MPG-peptide) was used to inhibit HIF1α expression. These findings provided information on PRMT3 signaling pathway and HIF1/VEGFA signaling pathway and offer a novel therapeutic strategy for colorectal cancer, mainly for treatment of anti-angiogenesis resistance patients.Subject terms: Gastrointestinal cancer, Cell biology 相似文献
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Protein arginine N-methyltransferases (PRMTs) act in signaling pathways and gene expression by methylating arginine residues within target proteins. PRMT1 is responsible for most cellular arginine methylation activity and can work independently or in collaboration with other PRMTs. In this study, we demonstrate a direct interaction between PRMT1 and PRMT2 using co-immunoprecipitation, bimolecular fluorescence complementation, and enzymatic assays. As a result of this interaction, PRMT2 stimulated PRMT1 activity, affecting its apparent V(max) and K(M) values in vitro and increasing the production of methylarginines in cells. Active site mutations and regional deletions from PRMT1 and -2 were also investigated, which demonstrated that complex formation required full-length, active PRMT1. Although the inhibition of methylation by adenosine dialdehyde prevented the interaction between PRMT1 and -2, it did not prevent the interaction between PRMT1 and a truncation mutant of PRMT2 lacking its Src homology 3 (SH3) domain. This result suggests that the SH3 domain may mediate an interaction between PRMT1 and -2 in a methylation-dependent fashion. On the basis of our findings, we propose that PRMT1 serves as the major methyltransferase in cells by forming higher-order oligomers with itself, PRMT2, and possibly other PRMTs. 相似文献