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1.
A. Shukla P. Chaurasia S. R. Bhaumik 《Cellular and molecular life sciences : CMLS》2009,66(8):1419-1433
Methylation of lysine residues of histones is associated with functionally distinct regions of chromatin, and, therefore,
is an important epigenetic mark. Over the past few years, several enzymes that catalyze this covalent modification on different
lysine residues of histones have been discovered. Intriguingly, histone lysine methylation has also been shown to be cross-regulated
by histone ubiquitination or the enzymes that catalyze this modification. These covalent modifications and their cross-talks
play important roles in regulation of gene expression, heterochromatin formation, genome stability, and cancer. Thus, there
has been a very rapid progress within past several years towards elucidating the molecular basis of histone lysine methylation
and ubiquitination, and their aberrations in human diseases. Here, we discuss these covalent modifications with their cross-regulation
and roles in controlling gene expression and stability.
Received 24 September 2008; received after revision 21 November 2008; accepted 28 November 2008 相似文献
2.
Epigenetic mechanisms in mammals 总被引:11,自引:1,他引:10
DNA and histone methylation are linked and subjected to mitotic inheritance in mammals. Yet how methylation is propagated
and maintained between successive cell divisions is not fully understood. A series of enzyme families that can add methylation
marks to cytosine nucleobases, and lysine and arginine amino acid residues has been discovered. Apart from methyltransferases,
there are also histone modification enzymes and accessory proteins, which can facilitate and/or target epigenetic marks. Several
lysine and arginine demethylases have been discovered recently, and the presence of an active DNA demethylase is speculated
in mammalian cells. A mammalian methyl DNA binding protein MBD2 and de novo DNA methyltransferase DNMT3A and DNMT3B are shown experimentally to possess DNA demethylase activity. Thus, complex mammalian
epigenetic mechanisms appear to be dynamic yet reversible along with a well-choreographed set of events that take place during
mammalian development. 相似文献
3.
4.
DNA methylation is a stable but not irreversible epigenetic signal that silences gene expression. It has a variety of important functions in mammals, including control of gene expression, cellular differentiation and development, preservation of chromosomal integrity, parental imprinting and X-chromosome inactivation. In addition, it has been implicated in brain function and the development of the immune system. Somatic alterations in genomic methylation patterns contribute to the etiology of human cancers and ageing. It is tightly interwoven with the modification of histone tails and other epigenetic signals. Here we review our current understanding of the molecular enzymology of the mammalian DNA methyltransferases Dnmt1, Dnmt3a, Dnmt3b and Dnmt2 and the roles of the enzymes in the above-mentioned biological processes. 相似文献
5.
Silencing of DNA repair genes plays a critical role in the development of the cancer because these genes, functioning normally, would prevent the accumulation of mutations leading to carcinogenesis. Epigenetic gene silencing is an alternative mechanism to genetic gene aberration, inactivating those genes in cancer. DNA methylation and histone modification are the major factors for epigenetic regulation of gene expression. Here, we describe recent advances in understanding of epigenetic silencing of DNA repair genes and their epigenetic mechanisms involving DNA methylation and histone modification. 相似文献
6.
Roth L Koncina E Satkauskas S Crémel G Aunis D Bagnard D 《Cellular and molecular life sciences : CMLS》2009,66(4):649-666
The semaphorin family is a large group of proteins controlling cell migration and axonal growth cone guidance. These proteins
are bi-functional signals capable of growth promotion or growth inhibition. Initially described in the nervous system, the
majority of studies related to semaphorins and semaphorin signalling are nowadays performed in model systems outside the nervous
system. Here, we provide an exhaustive review of the many faces of semaphorins both during developmental, regulatory and pathological
processes. Indeed, because of their crucial fundamental roles, the semaphorins and their receptors represent important targets
for the development of drugs directed at a variety of diseases.
Received 22 August 2008; received after revision 22 September 2008; accepted 24 September 2008
L. Roth, E. Koncina, S. Satkauskas: These authors contributed equally to this work. 相似文献
7.
Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels belong to the superfamily of voltage-gated pore loop channels. HCN channels are unique among
vertebrate voltage-gated ion channels, in that they have a reverse voltage-dependence that leads to activation upon hyperpolarization.
In addition, voltage-dependent opening of these channels is directly regulated by the binding of cAMP. HCN channels are encoded
by four genes (HCN1–4) and are widely expressed throughout the heart and the central nervous system. The current flowing through
HCN channels, designated Ih or If, plays a key role in the control of cardiac and neuronal rhythmicity (“pacemaker current”). In addition, Ih contributes to several other neuronal processes, including determination of resting membrane potential, dendritic integration
and synaptic transmission. In this review we give an overview on structure, function and regulation of HCN channels. Particular
emphasis will be laid on the complex roles of these channels for neuronal function and cardiac rhythmicity.
Received 22 August 2008; received after revision 22 September 2008; accepted 24 September 2008 相似文献
8.
Wang Y Guan X Fok KL Li S Zhang X Miao S Zong S Koide SS Chan HC Wang L 《Cellular and molecular life sciences : CMLS》2008,65(23):3822-3829
Rhomboid family members are widely conserved and found in all three kingdoms of life. They are serine proteases and serve
important regulatory functions. In the present study, a novel gene highly expressed in the testis, RHBDD1, is shown to be
a new member of the Rhomboid family, participating in the cleavage of BIK, a proapoptotic member of the Bcl-2 family. The
RHBDD1-involved proteolytic modification is upstream of the BIK protein degradation pathway. Mutagenesis studies show that
the amino acid residues glycine142 and serine144 of RHBDD1 are crucial for its activity in cleaving BIK at a site located
in the transmembrane region. Overexpression or knock-down of RHBDD1 in HEK 293T cells can reduce or enhance BIK-mediated apoptosis,
respectively. The present findings suggest that, by acting as a serine protease, RHBDD1 modulates BIK-mediated apoptotic activity.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Received 31 July 2008; received after revision 16 September 2008; accepted 19 September 2008 相似文献
9.
Santoro R 《Cellular and molecular life sciences : CMLS》2005,62(18):2067-2079
10.
A. C. S. Souza S. Azoubel K. C. S. Queiroz M. P. Peppelenbosch C. V. Ferreira 《Cellular and molecular life sciences : CMLS》2009,66(7):1140-1153
Reversible tyrosine phosphorylation is a key posttranslational regulatory modification of proteins in all eukaryotic cells
in normal and pathological processes. Recently a pivotal janus-faced biological role of the low molecular weight protein tyrosine
phosphatase (LMWPTP) has become clear. On the one hand this enzyme is important in facilitating appropriate immune responses
towards infectious agents, on the other hand it mediates exaggerated inflammatory responses toward innocuous stimuli. The
evidence that LMWPTP plays a role in oncological processes has added a promising novel angle. In this review we shall focus
on the regulation of LMWPTP enzymatic activity of signaling pathways of different immunological cells, the relation between
genetic polymorphism of LMWPTP and predisposition to some type of inflammatory disorders and the contribution of this enzyme
to cancer cell onset, growth and migration. Therefore, the LMWPTP is an interesting target for pharmacological intervention,
thus modifying both inappropriate cellular immune responses and cancer cell aggressiveness.
Received 15 August 2008; received after revision 06 October 2008; accepted 14 October 2008 相似文献
11.
Reticulons (RTNs) are membrane-spanning proteins sharing a typical domain named reticulon homology domain (RHD). RTN genes
have been identified in all eukaryotic organisms examined so far, and the corresponding proteins have been found predominantly
associated to the endoplasmic reticulum membranes. In animal and yeast, in which knowledge of the protein family is more advanced,
RTNs are involved in numerous cellular processes such as apoptosis, cell division and intracellular trafficking. Up to now,
a little attention has been paid to their plant counterparts, i.e., RTNLBs. In this review, we summarize the data available for RTNLB proteins and, using the data obtained with animal and
yeast models, several functions for RTNLBs in plant cells are proposed and discussed.
Received 01 July 2008; received after revision 08 September 2008; accepted 30 September 2008 相似文献
12.
Methionine adenosyltransferases (MATs) are the family of enzymes that synthesize the main biological methyl donor, S-adenosylmethionine. The high sequence conservation among catalytic subunits from bacteria and eukarya preserves key residues
that control activity and oligomerization, which is reflected in the protein structure. However, structural differences among
complexes with substrates and products have led to proposals of several reaction mechanisms. In parallel, folding studies
begin to explain how the three intertwined domains of the catalytic subunit are produced, and to highlight the importance
of certain intermediates in attaining the active final conformation. This review analyzes the available structural data and
proposes a consensus interpretation that facilitates an understanding of the pathological problems derived from impairment
of MAT function. In addition, new research opportunities directed toward clarification of aspects that remain obscure are
also identified.
Received 22 August 2008; received after revision 22 September 2008; accepted 26 September 2008 相似文献
13.
Some three decades have passed since the discovery of nucleosomes in 1974 and the first isolation of a histone chaperone in
1978. While various types of histone chaperones have been isolated and functionally analyzed, the elementary processes of
nucleosome assembly and disassembly have been less well characterized. Recently, the tertiary structure of a hetero-trimeric
complex composed of the histone chaperone CIA/ASF1 and the histone H3-H4 dimer was determined, and this complex was proposed
to be an intermediate in nucleosome assembly and disassembly reactions. In addition, CIA alone was biochemically shown to
dissociate the histone (H3-H4)2 tetramer into two histone H3-H4 dimers. This activity suggested that CIA regulates the semi-conservative replication of nucleosomes.
Here, we provide an overview of prominent histone chaperones with the goal of elucidating the mechanisms that preserve and
modify epigenetic information. We also discuss the reactions involved in nucleosome assembly and disassembly.
Received 5 July 2007; received after revision 8 September 2007; accepted 13 September 2007
M. Eitoku, L. Satoa: These authors contributed equally to this work. 相似文献
14.
15.
The anti-metabolite 5-fluorouracil (5-FU) is employed clinically to manage solid tumors including colorectal and breast cancer.
Intracellular metabolites of 5-FU can exert cytotoxic effects via inhibition of thymidylate synthetase, or through incorporation
into RNA and DNA, events that ultimately activate apoptosis. In this review, we cover the current data implicating DNA repair
processes in cellular responsiveness to 5-FU treatment. Evidence points to roles for base excision repair (BER) and mismatch
repair (MMR). However, mechanistic details remain unexplained, and other pathways have not been exhaustively interrogated.
Homologous recombination is of particular interest, because it resolves unrepaired DNA intermediates not properly dealt with
by BER or MMR. Furthermore, crosstalk among DNA repair pathways and S-phase checkpoint signaling has not been examined. Ongoing
efforts aim to design approaches and reagents that (i) approximate repair capacity and (ii) mediate strategic regulation of
DNA repair in order to improve the efficacy of current anticancer treatments.
Received 08 September 2008; received after revision 25 September 2008; accepted 03 October 2008 相似文献
16.
17.
Juste Wesche Sarah Kühn Benedikt M. Kessler Maayan Salton Alexander Wolf 《Cellular and molecular life sciences : CMLS》2017,74(18):3305-3315
Arginine methylation of histones is one mechanism of epigenetic regulation in eukaryotic cells. Methylarginines can also be found in non-histone proteins involved in various different processes in a cell. An enzyme family of nine protein arginine methyltransferases catalyses the addition of methyl groups on arginines of histone and non-histone proteins, resulting in either mono- or dimethylated-arginine residues. The reversibility of histone modifications is an essential feature of epigenetic regulation to respond to changes in environmental factors, signalling events, or metabolic alterations. Prominent histone modifications like lysine acetylation and lysine methylation are reversible. Enzyme family pairs have been identified, with each pair of lysine acetyltransferases/deacetylases and lysine methyltransferases/demethylases operating complementarily to generate or erase lysine modifications. Several analyses also indicate a reversible nature of arginine methylation, but the enzymes facilitating direct removal of methyl moieties from arginine residues in proteins have been discussed controversially. Differing reports have been seen for initially characterized putative candidates, like peptidyl arginine deiminase 4 or Jumonji-domain containing protein 6. Here, we review the most recent cellular, biochemical, and mass spectrometry work on arginine methylation and its reversible nature with a special focus on putative arginine demethylases, including the enzyme superfamily of Fe(II) and 2-oxoglutarate-dependent oxygenases. 相似文献
18.
Molecular and structural effects of inverse agonistic mutations on signaling of the thyrotropin receptor – a basally active GPCR 总被引:1,自引:0,他引:1
Kleinau G Jaeschke H Mueller S Worth CL Paschke R Krause G 《Cellular and molecular life sciences : CMLS》2008,65(22):3664-3676
Several mutations that decrease the basal signaling activity of G-protein coupled receptors (GPCRs) with pathogenic implications
are known. Here we study the molecular mechanisms responsible for this phenotype and investigate how basal and further activated
receptor conformations are interrelated. In the basally active thyroid stimulating hormone receptor (TSHR) we combined spatially-distant
mutations with opposing effects on basal activity in double-mutations and characterized mutant basal and TSH induced signaling.
Mutations lowering basal activity always have a suppressive influence on TSH induced signaling and on constitutively activating
mutations (CAMs). Our results suggest that the conformation of a basally ‘silenced’ GPCR might impair its intrinsic capacity
for signaling compared to the wild-type. Striking differences in conformation and intramolecular interactions between TSHR
models built using the crystal structures of inactive rhodopsin and partially active opsin help illuminate the molecular details
underlying mutations decreasing basal activity.
G. Kleinau, H. Jaeschke: These two authors contributed equally to this work.
Received 31 July 2008; received after revision 12 September 2008; accepted 19 September 2008 相似文献
19.
Hassan MI Waheed A Yadav S Singh TP Ahmad F 《Cellular and molecular life sciences : CMLS》2009,66(3):447-459
Prolactin inducible protein (PIP) is a 17- kDa single polypeptide chain, known by various names due to its versatile nature
and function in human reproductive and immunological systems. It is expressed in several exocrine tissues such as the lacrimal,
salivary, and sweat glands. Its expression is up regulated by prolactin and androgens, and estrogens down regulate it. Due
to its over-expression in metastatic breast and prostate cancer, presently PIP is considered as a prognostic biomarker. Moreover,
its aspartyl-proteinase nature suggests its role in tumor progression. PIP has unique features because it is small in size
and plays multiple important functions. Its ability to bind potentially with CD4-T cell receptor, immunoglobulin G (IgG),
actin, zinc α2-glycoprotein (ZAG), fibronectin and enamel pellicle, reveals its important biological functions. This is the
first comprehensive review on the structure and functional analysis of PIP and its clinical applications.
Received 04 August 2008; received after revision 09 September 2008; accepted 15 September 2008 相似文献
20.
DNA methylation and the regulation of gene transcription 总被引:28,自引:0,他引:28