Alessandra Montecucco
Istituto di Genetica Molecolare “Luigi Luca Cavalli-Sforza”
Via Abbiategrasso, 207 – 27100 PAVIA
Phone: +39 0382 546351
E-mail: alessandra.montecucco@igm.cnr.it
Curriculum Vitae – Download
Complete List of Publications – Download
Research Activity
BIOCHEMICAL AND FUNCTIONAL CHARACTERIZATION OF ATP-DEPENDENT DNA LIGASES
DNA ligases catalyze the joining of single-strand or double-strand breaks between adjacent 3’-hydroxyl and 5’-phosphate termini in the phosphodiester backbone of double-strand DNA. For this reason, they play a vital role in DNA metabolism. Most eukaryotic DNA ligases use ATP as a cofactor. In mammalian cells there are three DNA ligases called DNA ligase I, III and IV. DNA strand breaks can occur as a result either of the direct action of DNA damaging agents or as reaction intermediates during DNA replication, repair and recombination; therefore, the sealing of these breaks by DNA ligase is critical for maintaining genome integrity. Most of the work carried out in my laboratory has led to the characterization of human DNA ligase I that is required for chromosomal DNA replication as well as for DNA-repair pathways. We showed that DNA ligase I-deficiency leads to replication stress, elicits the activation of ATM checkpoint pathway and triggers phosphorylation of histone variant H2AX. We applied OMICS approaches to investigate the impact of replication stress on chromatin organization and gene expression.
We are currently using DNA ligase I-defective cell lines, produced and characterized in my laboratory, as a model system to study the interactions between DNA replication, RNA metabolism and chromatin organization in the cellular response to replicative stress.
DNA REPLICATION
In mammalian cells DNA replication takes place at discrete nuclear sites called replication foci where newly synthesized DNA accumulates. Colocalization on replication foci of replicative enzymes gave rise to the idea that replication takes place within factories. The number and size of the replication factories vary throughout S phase according to a program that reflects the replication of various portions of the genome. Our group contributed to the analysis of several aspects. We have identified a short motif, that we called replication factory targeting sequence (RFTS), as the determinant sufficient to target DNA ligase I to replication factories. The identification of the RFTS opens the possibility to disassemble the factories by targeting specific peptides. This perspective could be relevant in the search of new anti-proliferative drugs. The RFTS overlaps an evolutionary conserved binding site for PCNA. We have also shown that cell cycle dependent phosphorylation of DNA ligase I is involved in the dynamic program of replication factories. Finally, we have shown that the ordered assembly and disassembly of replication factories is monitored by the cell cycle checkpoints and that the type of DNA damage, its distribution relative to the moving fork and the mechanism involved in the DNA damage recognition could determine the choice between stabilization and dispersal of replication factories in S phase.
DNA DAMAGE RESPONSE IN NON-REPLICATING CELLS
Genome integrity is threatened by endogenous and exogenous sources of DNA damage including reactive oxygen species (ROS) produced by cell metabolism. Cells respond to DNA damage by activating the DNA damage response (DDR), a signalling pathway that senses the damage and transduces the signal to effector proteins. The molecular mechanisms that sustain DDR have been mostly studied in proliferating cells were two main apical protein kinases, ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related kinase), are activated in response to double stranded DNA breaks and stalling of replication forks, respectively. Their activation leads to transient cell cycle arrest and activation of DNA damage repair mechanisms. Unlike proliferating cells, little is known about the events activating DDR in terminally differentiated cells. Non-replicating cells are hardly replaceable, thus accumulation of DNA damage that leads to cell senescence or apoptosis is detrimental for the organism resulting in loss of tissue functions. This is exemplified in neurodegenerative diseases, in which DNA damage is now considered a hallmark of ageing neurons and neurodegeneration.
We are studying the events activating the DNA damage response in terminally differentiated cells, evaluating the response of neurons to endogenous sources of DNA damage caused by mitochondrial dysfunction and fatty acids that mimic hypercaloric diet.
Recent Publications
2022
|
Capanni C; Schena E; Di Giampietro ML; Montecucco A; Mattioli E; Lattanzi G The role of prelamin A post-translational maturation in stress response and 53BP1 recruitment Journal Article In: Frontiers in cell and developmental biology, vol. 10, 2022. @article{%a1.%Yb_44,
title = {The role of prelamin A post-translational maturation in stress response and 53BP1 recruitment},
author = {Capanni C and Schena E and Di Giampietro ML and Montecucco A and Mattioli E and Lattanzi G},
url = {https://www.frontiersin.org/articles/10.3389/fcell.2022.1018102/full},
doi = {10.3389/fcell.2022.1018102},
year = {2022},
date = {2022-03-31},
journal = {Frontiers in cell and developmental biology},
volume = {10},
abstract = {Lamin A is a main constituent of the nuclear lamina and contributes to nuclear shaping, mechano-signaling transduction and gene regulation, thus affecting major cellular processes such as cell cycle progression and entry into senescence, cellular differentiation and stress response. The role of lamin A in stress response is particularly intriguing, yet not fully elucidated, and involves prelamin A post-translational processing. Here, we propose prelamin A as the tool that allows lamin A plasticity during oxidative stress response and permits timely 53BP1 recruitment to DNA damage foci. We show that while PCNA ubiquitination, p21 decrease and H2AX phosphorylation occur soon after stress induction in the absence of prelamin A, accumulation of non-farnesylated prelamin A follows and triggers recruitment of 53BP1 to lamin A/C complexes. Then, the following prelamin A processing steps causing transient accumulation of farnesylated prelamin A and maturation to lamin A reduce lamin A affinity for 53BP1 and favor its release and localization to DNA damage sites. Consistent with these observations, accumulation of prelamin A forms in cells under basal conditions impairs histone H2AX phosphorylation, PCNA ubiquitination and p21 degradation, thus affecting the early stages of stress response. As a whole, our results are consistent with a physiological function of prelamin A modulation during stress response aimed at timely recruitment/release of 53BP1 and other molecules required for DNA damage repair. In this context, it becomes more obvious how farnesylated prelamin A accumulation to toxic levels alters timing of DNA damage signaling and 53BP1 recruitment, thus contributing to cellular senescence and accelerated organismal aging as observed in progeroid laminopathies.},
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Lamin A is a main constituent of the nuclear lamina and contributes to nuclear shaping, mechano-signaling transduction and gene regulation, thus affecting major cellular processes such as cell cycle progression and entry into senescence, cellular differentiation and stress response. The role of lamin A in stress response is particularly intriguing, yet not fully elucidated, and involves prelamin A post-translational processing. Here, we propose prelamin A as the tool that allows lamin A plasticity during oxidative stress response and permits timely 53BP1 recruitment to DNA damage foci. We show that while PCNA ubiquitination, p21 decrease and H2AX phosphorylation occur soon after stress induction in the absence of prelamin A, accumulation of non-farnesylated prelamin A follows and triggers recruitment of 53BP1 to lamin A/C complexes. Then, the following prelamin A processing steps causing transient accumulation of farnesylated prelamin A and maturation to lamin A reduce lamin A affinity for 53BP1 and favor its release and localization to DNA damage sites. Consistent with these observations, accumulation of prelamin A forms in cells under basal conditions impairs histone H2AX phosphorylation, PCNA ubiquitination and p21 degradation, thus affecting the early stages of stress response. As a whole, our results are consistent with a physiological function of prelamin A modulation during stress response aimed at timely recruitment/release of 53BP1 and other molecules required for DNA damage repair. In this context, it becomes more obvious how farnesylated prelamin A accumulation to toxic levels alters timing of DNA damage signaling and 53BP1 recruitment, thus contributing to cellular senescence and accelerated organismal aging as observed in progeroid laminopathies. |
2020
|
Giordano M; Infantino L; Biggiogera M; Montecucco A; Biamonti G Heat Shock Affects Mitotic Segregation of Human Chromosomes Bound to Stress-Induced Satellite III RNAs Journal Article In: International journal of molecular sciences, vol. 21, no. 8, pp. 2812, 2020. @article{%a1:%Y__510,
title = {Heat Shock Affects Mitotic Segregation of Human Chromosomes Bound to Stress-Induced Satellite III RNAs},
author = {Giordano M and Infantino L and Biggiogera M and Montecucco A and Biamonti G},
url = {https://www.mdpi.com/1422-0067/21/8/2812},
doi = {10.3390/ijms21082812},
year = {2020},
date = {2020-04-02},
journal = {International journal of molecular sciences},
volume = {21},
number = {8},
pages = {2812},
abstract = {Heat shock activates the transcription of arrays of Satellite III (SatIII) DNA repeats in the pericentromeric heterochromatic domains of specific human chromosomes, the longest of which is on chromosome 9. Long non-coding SatIII RNAs remain associated with transcription sites where they form nuclear stress bodies or nSBs. The biology of SatIII RNAs is still poorly understood. Here, we show that SatIII RNAs and nSBs are detectable up to four days after thermal stress and are linked to defects in chromosome behavior during mitosis. Heat shock perturbs the execution of mitosis. Cells reaching mitosis during the first 3 h of recovery accumulate in pro-metaphase. During the ensuing 48 h, this block is no longer detectable; however, a significant fraction of mitoses shows chromosome segregation defects. Notably, most of lagging chromosomes and chromosomal bridges are bound to nSBs and contain arrays of SatIII DNA. Disappearance of mitotic defects at the end of day 2 coincides with the processing of long non-coding SatIII RNAs into a ladder of small RNAs associated with chromatin and ranging in size from 25 to 75 nt. The production of these molecules does not rely on DICER and Argonaute 2 components of the RNA interference apparatus. Thus, massive transcription of SatIII DNA may contribute to chromosomal instability},
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Heat shock activates the transcription of arrays of Satellite III (SatIII) DNA repeats in the pericentromeric heterochromatic domains of specific human chromosomes, the longest of which is on chromosome 9. Long non-coding SatIII RNAs remain associated with transcription sites where they form nuclear stress bodies or nSBs. The biology of SatIII RNAs is still poorly understood. Here, we show that SatIII RNAs and nSBs are detectable up to four days after thermal stress and are linked to defects in chromosome behavior during mitosis. Heat shock perturbs the execution of mitosis. Cells reaching mitosis during the first 3 h of recovery accumulate in pro-metaphase. During the ensuing 48 h, this block is no longer detectable; however, a significant fraction of mitoses shows chromosome segregation defects. Notably, most of lagging chromosomes and chromosomal bridges are bound to nSBs and contain arrays of SatIII DNA. Disappearance of mitotic defects at the end of day 2 coincides with the processing of long non-coding SatIII RNAs into a ladder of small RNAs associated with chromatin and ranging in size from 25 to 75 nt. The production of these molecules does not rely on DICER and Argonaute 2 components of the RNA interference apparatus. Thus, massive transcription of SatIII DNA may contribute to chromosomal instability |
2019
|
Magni M; Buscemi G; Maita L; Peng L; Chan SY; Montecucco A; Delia D; Zannini L TSPYL2 is a novel regulator of SIRT1 and p300 activity in response to DNA damage. Journal Article In: Cell death and differentiation, vol. 26, no. 5, pp. 918-931, 2019. @article{%a1:%Y_79,
title = {TSPYL2 is a novel regulator of SIRT1 and p300 activity in response to DNA damage.},
author = {Magni M and Buscemi G and Maita L and Peng L and Chan SY and Montecucco A and Delia D and Zannini L},
url = {https://www.nature.com/articles/s41418-018-0168-6},
doi = {10.1038/s41418-018-0168-6},
year = {2019},
date = {2019-03-06},
journal = {Cell death and differentiation},
volume = {26},
number = {5},
pages = {918-931},
abstract = {Protein acetylation and deacetylation events are finely regulated by lysine-acetyl-transferases and lysine-deacetylases and constitute an important tool for the activation or inhibition of specific cellular pathways. One of the most important lysine-acetyl-transferases is p300, which is involved in the regulation of gene expression, cell growth, DNA repair, differentiation, apoptosis, and tumorigenesis. A well-known target of p300 is constituted by the tumor suppressor protein p53, which plays a critical role in the maintenance of genomic stability and whose activity is known to be controlled by post-translational modifications, among which acetylation. p300 activity toward p53 is negatively regulated by the NAD-dependent deacetylase SIRT1, which deacetylates p53 preventing its transcriptional activation and the induction of p53-dependent apoptosis. However, the mechanisms responsible for p53 regulation by p300 and SIRT1 are still poorly understood. Here we identify the nucleosome assembly protein TSPY-Like 2 (TSPYL2, also known as TSPX, DENTT, and CDA1) as a novel regulator of SIRT1 and p300 function. We demonstrate that, upon DNA damage, TSPYL2 inhibits SIRT1, disrupting its association with target proteins, and promotes p300 acetylation and activation, finally stimulating p53 acetylation and p53-dependent cell death. Indeed, in response to DNA damage, cells silenced for TSPYL2 were found to be defective in p53 activation and apoptosis induction and these events were shown to be dependent on SIRT1 and p300 function. Collectively, our results shed new light on the regulation of p53 acetylation and activation and reveal a novel TSPYL2 function with important implications in cancerogenesis.},
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Protein acetylation and deacetylation events are finely regulated by lysine-acetyl-transferases and lysine-deacetylases and constitute an important tool for the activation or inhibition of specific cellular pathways. One of the most important lysine-acetyl-transferases is p300, which is involved in the regulation of gene expression, cell growth, DNA repair, differentiation, apoptosis, and tumorigenesis. A well-known target of p300 is constituted by the tumor suppressor protein p53, which plays a critical role in the maintenance of genomic stability and whose activity is known to be controlled by post-translational modifications, among which acetylation. p300 activity toward p53 is negatively regulated by the NAD-dependent deacetylase SIRT1, which deacetylates p53 preventing its transcriptional activation and the induction of p53-dependent apoptosis. However, the mechanisms responsible for p53 regulation by p300 and SIRT1 are still poorly understood. Here we identify the nucleosome assembly protein TSPY-Like 2 (TSPYL2, also known as TSPX, DENTT, and CDA1) as a novel regulator of SIRT1 and p300 function. We demonstrate that, upon DNA damage, TSPYL2 inhibits SIRT1, disrupting its association with target proteins, and promotes p300 acetylation and activation, finally stimulating p53 acetylation and p53-dependent cell death. Indeed, in response to DNA damage, cells silenced for TSPYL2 were found to be defective in p53 activation and apoptosis induction and these events were shown to be dependent on SIRT1 and p300 function. Collectively, our results shed new light on the regulation of p53 acetylation and activation and reveal a novel TSPYL2 function with important implications in cancerogenesis. |
2018
|
Biamonti G; Maita L; Montecucco A The Krebs Cycle Connection: Reciprocal Influence Between Alternative Splicing Programs and Cell Metabolism. Journal Article In: Frontiers in oncology, vol. 8, pp. 408, 2018. @article{%a1:%Y_114,
title = {The Krebs Cycle Connection: Reciprocal Influence Between Alternative Splicing Programs and Cell Metabolism.},
author = {Biamonti G and Maita L and Montecucco A},
url = {https://www.frontiersin.org/articles/10.3389/fonc.2018.00408/full},
doi = {10.3389/fonc.2018.00408},
year = {2018},
date = {2018-09-26},
journal = {Frontiers in oncology},
volume = {8},
pages = {408},
abstract = {Alternative splicing is a pervasive mechanism that molds the transcriptome to meet cell and organism needs. However, how this layer of gene expression regulation is coordinated with other aspects of the cell metabolism is still largely undefined. Glucose is the main energy and carbon source of the cell. Not surprisingly, its metabolism is finely tuned to satisfy growth requirements and in response to nutrient availability. A number of studies have begun to unveil the connections between glucose metabolism and splicing programs. Alternative splicing modulates the ratio between M1 and M2 isoforms of pyruvate kinase in this way determining the choice between aerobic glycolysis and complete glucose oxidation in the Krebs cycle. Reciprocally, intermediates in the Krebs cycle may impact splicing programs at different levels by modulating the activity of 2-oxoglutarate-dependent oxidases. In this review we discuss the molecular mechanisms that coordinate alternative splicing programs with glucose metabolism, two aspects with profound implications in human diseases.},
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Alternative splicing is a pervasive mechanism that molds the transcriptome to meet cell and organism needs. However, how this layer of gene expression regulation is coordinated with other aspects of the cell metabolism is still largely undefined. Glucose is the main energy and carbon source of the cell. Not surprisingly, its metabolism is finely tuned to satisfy growth requirements and in response to nutrient availability. A number of studies have begun to unveil the connections between glucose metabolism and splicing programs. Alternative splicing modulates the ratio between M1 and M2 isoforms of pyruvate kinase in this way determining the choice between aerobic glycolysis and complete glucose oxidation in the Krebs cycle. Reciprocally, intermediates in the Krebs cycle may impact splicing programs at different levels by modulating the activity of 2-oxoglutarate-dependent oxidases. In this review we discuss the molecular mechanisms that coordinate alternative splicing programs with glucose metabolism, two aspects with profound implications in human diseases. |
2017
|
Pignataro D; Francia S; Zanetta F; Brenna G; Brandini S; Olivieri A; Torroni A; Biamonti G; Montecucco A A missense MT-ND5 mutation in differentiated Parkinson Disease cytoplasmic hybrid induces ROS-dependent DNA Damage Response amplified by DROSHA. Journal Article In: Scientific reports, vol. 7, no. 1, pp. 9528, 2017. @article{%a1:%Y_214,
title = {A missense MT-ND5 mutation in differentiated Parkinson Disease cytoplasmic hybrid induces ROS-dependent DNA Damage Response amplified by DROSHA.},
author = {Pignataro D and Francia S and Zanetta F and Brenna G and Brandini S and Olivieri A and Torroni A and Biamonti G and Montecucco A},
url = {https://www.nature.com/articles/s41598-017-09910-x},
doi = {10.1038/s41598-017-09910-x},
year = {2017},
date = {2017-02-22},
journal = {Scientific reports},
volume = {7},
number = {1},
pages = {9528},
abstract = {Genome integrity is continuously threatened by endogenous sources of DNA damage including reactive oxygen species (ROS) produced by cell metabolism. Factors of the RNA interference (RNAi) machinery have been recently involved in the cellular response to DNA damage (DDR) in proliferating cells. To investigate the impact of component of RNAi machinery on DDR activation in terminally differentiated cells, we exploited cytoplasmic hybrid (cybrid) cell lines in which mitochondria of sporadic Parkinson's disease patients repopulate neuroblastoma SH-SY5Y-Rho(0) cells. Upon differentiation into dopaminergic neuron-like cells, PD63 cybrid showed increased intracellular level of ROS and chronic DDR activation, compared to other cybrids with the same nuclear background. Importantly, DDR activation in these cells can be prevented by ROS scavenging treatment suggesting that ROS production is indeed causative of nuclear DNA damage. Sequence analysis of the mitogenomes identified a rare and heteroplasmic missense mutation affecting a highly conserved residue of the ND5-subunit of respiratory complex I, which accounts for ROS increase. We demonstrated that the assembly of nuclear DDR foci elicited by oxidative stress in these cells relies on DROSHA, providing the first evidence that components of RNAi machinery play a crucial role also in the mounting of ROS-induced DDR in non-replicating neuronal cells.},
keywords = {},
pubstate = {published},
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Genome integrity is continuously threatened by endogenous sources of DNA damage including reactive oxygen species (ROS) produced by cell metabolism. Factors of the RNA interference (RNAi) machinery have been recently involved in the cellular response to DNA damage (DDR) in proliferating cells. To investigate the impact of component of RNAi machinery on DDR activation in terminally differentiated cells, we exploited cytoplasmic hybrid (cybrid) cell lines in which mitochondria of sporadic Parkinson's disease patients repopulate neuroblastoma SH-SY5Y-Rho(0) cells. Upon differentiation into dopaminergic neuron-like cells, PD63 cybrid showed increased intracellular level of ROS and chronic DDR activation, compared to other cybrids with the same nuclear background. Importantly, DDR activation in these cells can be prevented by ROS scavenging treatment suggesting that ROS production is indeed causative of nuclear DNA damage. Sequence analysis of the mitogenomes identified a rare and heteroplasmic missense mutation affecting a highly conserved residue of the ND5-subunit of respiratory complex I, which accounts for ROS increase. We demonstrated that the assembly of nuclear DDR foci elicited by oxidative stress in these cells relies on DROSHA, providing the first evidence that components of RNAi machinery play a crucial role also in the mounting of ROS-induced DDR in non-replicating neuronal cells. |
2016
|
Montecucco A; Biamonti G DNA and RNA metabolism meet at chromatin to control genome stability Journal Article In: Frontiers in Genetics, vol. 7, pp. 67, 2016. @article{%a1:%Y_300,
title = {DNA and RNA metabolism meet at chromatin to control genome stability},
author = {Montecucco A and Biamonti G},
url = {http://journal.frontiersin.org/article/10.3389/fgene.2016.00067/full},
doi = {doi: 10.3389/fgene.2016.00067},
year = {2016},
date = {2016-02-19},
journal = {Frontiers in Genetics},
volume = {7},
pages = {67},
keywords = {},
pubstate = {published},
tppubtype = {article}
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|
2015
|
Cremaschi P; Oliverio M; Leva V; Bione S; Carriero R; Mazzucco G; Palamidessi A; Scita G; Biamonti G; Montecucco A Chronic Replication Problems Impact Cell Morphology and Adhesion of DNA Ligase I Defective Cells. Journal Article In: Plos One, vol. 10, no. 7, pp. e0130561, 2015. @article{%a1:%Y_346,
title = {Chronic Replication Problems Impact Cell Morphology and Adhesion of DNA Ligase I Defective Cells.},
author = {Cremaschi P and Oliverio M and Leva V and Bione S and Carriero R and Mazzucco G and Palamidessi A and Scita G and Biamonti G and Montecucco A},
url = {https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130561},
doi = {10.1371/journal.pone.0130561},
year = {2015},
date = {2015-02-04},
journal = {Plos One},
volume = {10},
number = {7},
pages = {e0130561},
abstract = {Moderate DNA damage resulting from metabolic activities or sub-lethal doses of exogenous insults may eventually lead to cancer onset. Human 46BR.1G1 cells bear a mutation in replicative DNA ligase I (LigI) which results in low levels of replication-dependent DNA damage. This replication stress elicits a constitutive phosphorylation of the ataxia telangiectasia mutated (ATM) checkpoint kinase that fails to arrest cell cycle progression or to activate apoptosis or cell senescence. Stable transfection of wild type LigI, as in 7A3 cells, prevents DNA damage and ATM activation. Here we show that parental 46BR.1G1 and 7A3 cells differ in important features such as cell morphology, adhesion and migration. Comparison of gene expression profiles in the two cell lines detects Bio-Functional categories consistent with the morphological and migration properties of LigI deficient cells. Interestingly, ATM inhibition makes 46BR.1G1 more similar to 7A3 cells for what concerns morphology, adhesion and expression of cell-cell adhesion receptors. These observations extend the influence of the DNA damage response checkpoint pathways and unveil a role for ATM kinase activity in modulating cell biology parameters relevant to cancer progression.},
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Moderate DNA damage resulting from metabolic activities or sub-lethal doses of exogenous insults may eventually lead to cancer onset. Human 46BR.1G1 cells bear a mutation in replicative DNA ligase I (LigI) which results in low levels of replication-dependent DNA damage. This replication stress elicits a constitutive phosphorylation of the ataxia telangiectasia mutated (ATM) checkpoint kinase that fails to arrest cell cycle progression or to activate apoptosis or cell senescence. Stable transfection of wild type LigI, as in 7A3 cells, prevents DNA damage and ATM activation. Here we show that parental 46BR.1G1 and 7A3 cells differ in important features such as cell morphology, adhesion and migration. Comparison of gene expression profiles in the two cell lines detects Bio-Functional categories consistent with the morphological and migration properties of LigI deficient cells. Interestingly, ATM inhibition makes 46BR.1G1 more similar to 7A3 cells for what concerns morphology, adhesion and expression of cell-cell adhesion receptors. These observations extend the influence of the DNA damage response checkpoint pathways and unveil a role for ATM kinase activity in modulating cell biology parameters relevant to cancer progression. |
Montecucco A; Zanetta F; Biamonti G Molecular mechanisms of etoposide. Journal Article In: EXCLI Journal, vol. 14, pp. 95-108, 2015. @article{%a1:%Y_382,
title = {Molecular mechanisms of etoposide.},
author = {Montecucco A and Zanetta F and Biamonti G},
url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4652635/},
doi = {10.17179/excli2015-561},
year = {2015},
date = {2015-01-19},
journal = {EXCLI Journal},
volume = {14},
pages = {95-108},
abstract = {Etoposide derives from podophyllotoxin, a toxin found in the American Mayapple. It was first synthesized in
1966 and approved for cancer therapy in 1983 by the U.S. Food and Drug Administration (Hande, 1998). Starting from 1980s several studies demonstrated that etoposide targets DNA topoisomerase II activities thus leading to the production of DNA breaks and eliciting a response that affects several aspects of cell metabolisms. In this review we will focus on molecular mechanisms that account for the biological effect of etoposide.},
keywords = {},
pubstate = {published},
tppubtype = {article}
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Etoposide derives from podophyllotoxin, a toxin found in the American Mayapple. It was first synthesized in
1966 and approved for cancer therapy in 1983 by the U.S. Food and Drug Administration (Hande, 1998). Starting from 1980s several studies demonstrated that etoposide targets DNA topoisomerase II activities thus leading to the production of DNA breaks and eliciting a response that affects several aspects of cell metabolisms. In this review we will focus on molecular mechanisms that account for the biological effect of etoposide. |
