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1.
Ignacio Campillo-Marcos Pedro A. Lazo 《Cellular and molecular life sciences : CMLS》2018,75(13):2375-2388
DNA damage causes a local distortion of chromatin that triggers the sequential processes that participate in specific DNA repair mechanisms. This initiation of the repair response requires the involvement of a protein whose activity can be regulated by histones. Kinases are candidates to regulate and coordinate the connection between a locally altered chromatin and the response initiating signals that lead to identification of the type of lesion and the sequential steps required in specific DNA damage responses (DDR). This initiating kinase must be located in chromatin, and be activated independently of the type of DNA damage. We review the contribution of the Ser-Thr vaccinia-related kinase 1 (VRK1) chromatin kinase as a new player in the signaling of DNA damage responses, at chromatin and cellular levels, and its potential as a new therapeutic target in oncology. VRK1 is involved in the regulation of histone modifications, such as histone phosphorylation and acetylation, and in the formation of γH2AX, NBS1 and 53BP1 foci induced in DDR. Induction of DNA damage by chemotherapy or radiation is a mainstay of cancer treatment. Therefore, novel treatments can be targeted to proteins implicated in the regulation of DDR, rather than by directly causing DNA damage. 相似文献
2.
The acquisition of an appropriate set of chemical modifications is required in order to establish correct structure of RNA molecules, and essential for their function. Modification of RNA bases affects RNA maturation, RNA processing, RNA quality control, and protein translation. Some RNA modifications are directly involved in the regulation of these processes. RNA epigenetics is emerging as a mechanism to achieve dynamic regulation of RNA function. Other modifications may prevent or be a signal for degradation. All types of RNA species are subject to processing or degradation, and numerous cellular mechanisms are involved. Unexpectedly, several studies during the last decade have established a connection between DNA and RNA surveillance mechanisms in eukaryotes. Several proteins that respond to DNA damage, either to process or to signal the presence of damaged DNA, have been shown to participate in RNA quality control, turnover or processing. Some enzymes that repair DNA damage may also process modified RNA substrates. In this review, we give an overview of the DNA repair proteins that function in RNA metabolism. We also discuss the roles of two base excision repair enzymes, SMUG1 and APE1, in RNA quality control. 相似文献
3.
Poeschla EM 《Cellular and molecular life sciences : CMLS》2008,65(9):1403-1424
HIV integrates a DNA copy of its genome into a host cell chromosome in each replication cycle. The essential DNA cleaving
and joining chemistry of integration is known, but there is less understanding of the process as it occurs in a cell, where
two complex and dynamic macromolecular entities are joined: the viral pre-integration complex and chromatin. Among implicated
cellular factors, much recent attention has coalesced around LEDGF/p75, a nuclear protein that may act as a chromatin docking
factor or receptor for lentiviral pre-integration complexes. LEDGF/p75 tethers HIV integrase to chromatin, protects it from
degradation, and strongly influences the genome-wide pattern of HIV integration. Depleting the protein from cells and/or over-expressing
its integrase-binding domain blocks viral replication. Current goals are to establish the underlying mechanisms and to determine
whether this knowledge can be exploited for antiviral therapy or for targeting lentiviral vector integration in human gene
therapy.
Received 25 November 2007; received after revision 7 January 2008; accepted 10 January 2008 相似文献
4.
Chromatin assembly during S phase: contributions from histone deposition, DNA replication and the cell division cycle 总被引:7,自引:0,他引:7
During S phase of the eukaryotic cell division cycle, newly replicated DNA is rapidly assembled into chromatin. Newly synthesised
histones form complexes with chromatin assembly factors, mediating their deposition onto nascent DNA and their assembly into
nucleosomes. Chromatin assembly factor 1, CAF-1, is a specialised assembly factor that targets these histones to replicating
DNA by association with the replication fork associated protein, proliferating cell nuclear antigen, PCNA. Nucleosomes are
further organised into ordered arrays along the DNA by the activity of ATP-dependent chromatin assembly and spacing factors
such as ATP-utilising chromatin assembly and remodelling factor ACF. An additional level of controlling chromatin assembly
pathways has become apparent by the observation of functional requirements for cyclin-dependent protein kinases, casein kinase
II and protein phosphatases. In this review, we will discuss replication-associated histone deposition and nucleosome assembly
pathways, and we will focus in particular on how nucleosome assembly is linked to DNA replication and how it may be regulated
by the cell cycle control machinery. 相似文献
5.
ATM protein kinase: the linchpin of cellular defenses to stress 总被引:1,自引:1,他引:0
Bhatti S Kozlov S Farooqi AA Naqi A Lavin M Khanna KK 《Cellular and molecular life sciences : CMLS》2011,68(18):2977-3006
ATM is the most significant molecule involved in monitoring the genomic integrity of the cell. Any damage done to DNA relentlessly
challenges the cellular machinery involved in recognition, processing and repair of these insults. ATM kinase is activated
early to detect and signal lesions in DNA, arrest the cell cycle, establish DNA repair signaling and faithfully restore the
damaged chromatin. ATM activation plays an important role as a barrier to tumorigenesis, metabolic syndrome and neurodegeneration.
Therefore, studies of ATM-dependent DNA damage signaling pathways hold promise for treatment of a variety of debilitating
diseases through the development of new therapeutics capable of modulating cellular responses to stress. In this review, we
have tried to untangle the complex web of ATM signaling pathways with the purpose of pinpointing multiple roles of ATM underlying
the complex phenotypes observed in AT patients. 相似文献
6.
Polyamines in cell growth and cell death: molecular mechanisms and therapeutic applications 总被引:30,自引:0,他引:30
Polyamines are aliphatic cations with multiple functions and are essential for life. Cellular polyamine levels are regulated by multiple pathways such as synthesis from amino acid precursors, cellular uptake mechanisms that salvage polyamines from diet and intestinal microorganisms, as well as stepwise degradation and efflux. Investigations using polyamine biosynthetic inhibitors indicate that alterations in cellular polyamine levels modulate normal and cancer cell growth. Studies using transgenic mice overexpressing polyamine biosynthetic enzymes support a role of polyamines in carcinogenesis. Many, if not all, signal transduction pathways intersect with polyamine biosynthetic pathways and the regulation of intracellular polyamine levels. Direct binding of polyamines to DNA and their ability to modulate DNA-protein interactions appear to be important in the molecular mechanisms of polyamine action in cell proliferation. Consistent with the role of polyamines as facilitators of cell growth, several studies have shown their ability to protect cells from apoptosis. However, polyamines also have a role in facilitating cell death. The basis of these diverse cellular responses is currently not known. Cell death response might be partly mediated by the production of hydrogen peroxide during polyamine catabolism. In addition, the ability of polyamines to alter DNA-protein and protein-protein interactions might be disruptive to cellular functions, when abnormally high levels are accumulated due to defects in polyamine catabolic or efflux pathways. A large body of data indicates that polyamine pathway can be a molecular target for therapeutic intervention in several types cancers. Inhibitors of biosynthesis, polyamine analogues as well as oligonucleotide/polyamine analogue combinations are promising drug candidates for chemoprevention and/or treatment of cancer. 相似文献
7.
Tsyba L Rynditch AV Boeri E Jabbari K Bernardi G 《Cellular and molecular life sciences : CMLS》2004,61(6):721-726
The localization of HIV-1 proviruses in compositional DNA fractions from 27 AIDS patients during the chronic phase of the disease with depletion of CD4+ and different levels of viremia showed the following. (1) At low viremia, proviruses are predominantly localized in the GC-richest isochores, which are characterized by an open chromatin structure; this result mimics findings on HIV-1 integration in early infected cells in culture. (2) At higher viremia, an increased distribution of proviruses in GC-poor isochores (which match the GC poorness of HIV-1) was found; this suggests a selection of cells in which the isopycnic localization leads to a higher expression of proviruses and, in turn, to higher viremia. (3) At the highest viremia, integrations in GC-rich isochores are often predominant again, but generally not at the same level as in (1); this may be the consequence of new integrations from the extremely abundant RNA copies.Received 21 November 2003; received after revision 13 January 2004: accepted 15 January 2004 相似文献
8.
Novel aspects of glypican glycobiology 总被引:5,自引:0,他引:5
Fransson LA Belting M Cheng F Jönsson M Mani K Sandgren S 《Cellular and molecular life sciences : CMLS》2004,61(9):1016-1024
Mutations in glypican genes cause dysmorphic and overgrowth syndromes in men and mice, abnormal development in flies and worms, and defective gastrulation in zebrafish and ascidians. All glypican core proteins share a characteristic pattern of 14 conserved cysteine residues. Upstream from the C-terminal membrane anchorage are 3–4 heparan sulfate attachment sites. Cysteines in glypican-1 can become nitrosylated by nitric oxide in a copper-dependent reaction. When glypican-1 is exposed to ascorbate, nitric oxide is released and participates in deaminative cleavage of heparan sulfate at sites where the glucosamines have a free amino group. This process takes place while glypican-1 recycles via a nonclassical, caveolin-1-associated route. Glypicans are involved in growth factor signalling and transport, e.g. of polyamines. Cargo can be unloaded from heparan sulfate by nitric oxide-dependent degradation. How glypican and its degradation products and the cargo exit from the recycling route is an enigma.Received 27 November 2003; received after revision 8 January 2004; accepted 13 January 2004 相似文献
9.
Ribosome-catalyzed peptide bond formation is a crucial function of all organisms. The ribosome is a ribonucleoprotein particle, with both RNA and protein components necessary for the various steps leading to protein biosynthesis. Evolutionary theory predicts an early environment devoid of complex biomolecules, and prebiotic peptide synthesis would have started in a simple way. A fundamental question regarding peptide synthesis is how the current ribosome-catalyzed reaction evolved from a primitive system. Here we look at both prebiotic and modern mechanisms of peptide bond formation and discuss recent experiments that aim to connect these activities. In particular, RNA can facilitate peptide bond formation by providing a template for activated amino acids to react and can catalyze a variety of functions that would have been necessary in a pre-protein world. Therefore, RNA may have facilitated the emergence of the current protein world from an RNA or even prebiotic world.Received 4 December 2003; received after revision 13 January 2004; accepted 15 January 2004 相似文献
10.
David S. Moura Ignacio Campillo-Marcos Marta Vázquez-Cedeira Pedro A. Lazo 《Cellular and molecular life sciences : CMLS》2018,75(14):2591-2611
Regulation of cell division requires the integration of signals implicated in chromatin reorganization and coordination of its sequential changes in mitosis. Vaccinia-related kinase 1 (VRK1) and Aurora B (AURKB) are two nuclear kinases involved in different steps of cell division. We have studied whether there is any functional connection between these two nuclear kinases, which phosphorylate histone H3 in Thr3 and Ser10, respectively. VRK1 and AURKB are able to form a stable protein complex, which represents only a minor subpopulation of each kinase within the cell and is detected following nocodazole release. Each kinase is able to inhibit the kinase activity of the other kinase, as well as inhibit their specific phosphorylation of histone H3. In locations where the two kinases interact, there is a different pattern of histone modifications, indicating that there is a local difference in chromatin during mitosis because of the local complexes formed by these kinases and their asymmetric intracellular distribution. Depletion of VRK1 downregulates the gene expression of BIRC5 (survivin) that recognizes H3-T3ph, both are dependent on the activity of VRK1, and is recovered with kinase active murine VRK1, but not with a kinase-dead protein. The H3–Thr3ph–survivin complex is required for AURB recruitment, and their loss prevents the localization of ACA and AURKB in centromeres. The cross inhibition of the kinases at the end of mitosis might facilitate the formation of daughter cells. A sequential role for VRK1, AURKB, and haspin in the progression of mitosis is proposed. 相似文献
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Polyamines are small charged molecules essential for various cellular functions, but at high levels they are cytotoxic. Two
yeast kinases, SKY1 and PTK2, have been demonstrated to regulate polyamine tolerance. Here we report the identification and
characterization of additional genes involved in regulating polyamine tolerance: YGL007W, FES1 and AGP2. Deletion of YGL007W,
an open reading frame located within the promoter of the membrane proton pump PMA1, decreased Pma1p expression. Deletion of
FES1 or AGP2 resulted in reduced polyamine uptake. While high-affinity spermine uptake was practically absent in agp2Δ cells, fes1Δ cells displayed only reduced affinity towards spermine. Despite the reduced uptake, the resistant strains accumulated significant
levels of polyamines and displayed increased ornithine decarboxylase activity, suggesting reduced polyamine sensing. Interestingly,
fes1Δ cells were highly sensitive to salt ions, suggesting different underlying mechanisms. These results indicate that mechanisms
leading to polyamine tolerance are complex, and involve components other than uptake.
Received 31 July 2005; received after revision 7 October 2005; accepted 19 October 2005 相似文献
14.
Izaurralde E 《Cellular and molecular life sciences : CMLS》2001,58(8):1105-1112
The distinguishing feature of eukaryotic cells is the segregation of RNA biogenesis and DNA replication in the nucleus, separate
from the cytoplasmic machinery for protein synthesis. As a consequence, messenger RNAs (mRNAs) and all cytoplasmic RNAs from
nuclear origin need to be transported from their site of synthesis in the nucleus to their final cytoplasmic destination.
Nuclear export occurs through nuclear pore complexes (NPCs) and is mediated by saturable transport receptors, which shuttle
between the nucleus and cytoplasm. The past years have seen great progress in the characterization of the mRNA export pathway
and the identification of proteins involved in this process. A novel family of nuclear export receptors (the NXF family),
distinct from the well-characterized family of importin β-like proteins, has been implicated in the export of mRNA to the cytoplasm.
Received 23 January 2001; received after revision 12 April 2001; accepted 12 April 2001 相似文献
15.
Leiman PG Kanamaru S Mesyanzhinov VV Arisaka F Rossmann MG 《Cellular and molecular life sciences : CMLS》2003,60(11):2356-2370
Bacteriophage T4 is one of the most complex viruses. More than 40 different proteins form the mature virion, which consists of a protein shell encapsidating a 172-kbp double-stranded genomic DNA, a tail, and fibers, attached to the distal end of the tail. The fibers and the tail carry the host cell recognition sensors and are required for attachment of the phage to the cell surface. The tail also serves as a channel for delivery of the phage DNA from the head into the host cell cytoplasm. The tail is attached to the unique portal vertex of the head through which the phage DNA is packaged during head assembly. Similar to other phages, and also herpes viruses, the unique vertex is occupied by a dodecameric portal protein, which is involved in DNA packaging.Received 18 February 2003; received after revision 16 April 2003; accepted 9 May 2003 相似文献
16.
C Jacq J Lazowska P P Slonimski 《Comptes rendus des séances de l'Académie des sciences. Série D, Sciences naturelles》1980,290(2):89-92
DNA sequence studies of mutated and wild type alleles of an intron in the mosaic mitochondrial gene for cytochrome b have revealed the possible existence of a protein coded in the intron and involved in RNA splicing. This protein would be endowed with properties of intrinsic autotomy of its own messenger RNA. 相似文献
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Santoro R 《Cellular and molecular life sciences : CMLS》2005,62(18):2067-2079
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