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Oscar Fernandez Capetillo

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https://www.readbyqxmd.com/read/27680696/erratum-replication-fork-stability-confers-chemoresistance-in-brca-deficient-cells
#1
Arnab Ray Chaudhuri, Elsa Callen, Xia Ding, Ewa Gogola, Alexandra A Duarte, Ji-Eun Lee, Nancy Wong, Vanessa Lafarga, Jennifer A Calvo, Nicholas J Panzarino, Sam John, Amanda Day, Anna Vidal Crespo, Binghui Shen, Linda M Starnes, Julian R de Ruiter, Jeremy A Daniel, Panagiotis A Konstantinopoulos, David Cortez, Sharon B Cantor, Oscar Fernandez-Capetillo, Kai Ge, Jos Jonkers, Sven Rottenberg, Shyam K Sharan, André Nussenzweig
No abstract text is available yet for this article.
September 28, 2016: Nature
https://www.readbyqxmd.com/read/27667742/a-sumo-and-ubiquitin-code-coordinates-protein-traffic-at-replication-factories
#2
Emilio Lecona, Oscar Fernandez-Capetillo
Post-translational modifications regulate each step of DNA replication to ensure the faithful transmission of genetic information. In this context, we recently showed that deubiquitination of SUMO2/3 and SUMOylated proteins by USP7 helps to create a SUMO-rich and ubiquitin-low environment around replisomes that is necessary to maintain the activity of replication forks and for new origin firing. We propose that a two-flag system mediates the collective concentration of factors at sites of DNA replication, whereby SUMO and Ubiquitinated-SUMO would constitute "stay" or "go" signals respectively for replisome and accessory factors...
September 26, 2016: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/27625305/targeting-the-kinase-activities-of-atr-and-atm-exhibits-antitumoral-activity-in-mouse-models-of-mll-rearranged-aml
#3
Isabel Morgado-Palacin, Amanda Day, Matilde Murga, Vanesa Lafarga, Marta Elena Anton, Anthony Tubbs, Hua-Tang Chen, Aysegul Ergan, Rhonda Anderson, Avinash Bhandoola, Kurt G Pike, Bernard Barlaam, Elaine Cadogan, Xi Wang, Andrew J Pierce, Chad Hubbard, Scott A Armstrong, André Nussenzweig, Oscar Fernandez-Capetillo
Among the various subtypes of acute myeloid leukemia (AML), those with chromosomal rearrangements of the MLL oncogene (AML-MLL) have a poor prognosis. AML-MLL tumor cells are resistant to current genotoxic therapies because of an attenuated response by p53, a protein that induces cell cycle arrest and apoptosis in response to DNA damage. In addition to chemicals that damage DNA, efforts have focused on targeting DNA repair enzymes as a general chemotherapeutic approach to cancer treatment. Here, we found that inhibition of the kinase ATR, which is the primary sensor of DNA replication stress, induced chromosomal breakage and death of mouse AML(MLL) cells (with an MLL-ENL fusion and a constitutively active N-RAS independently of p53...
September 13, 2016: Science Signaling
https://www.readbyqxmd.com/read/27577084/efficacy-of-atr-inhibitors-as-single-agents-in-ewing-sarcoma
#4
Maria Nieto-Soler, Isabel Morgado-Palacin, Vanesa Lafarga, Emilio Lecona, Matilde Murga, Elsa Callen, Daniel Azorin, Javier Alonso, Andres J Lopez-Contreras, Andre Nussenzweig, Oscar Fernandez-Capetillo
Ewing sarcomas (ES) are pediatric bone tumors that arise from a driver translocation, most frequently EWS/FLI1. Current ES treatment involves DNA damaging agents, yet the basis for the sensitivity to these therapies remains unknown. Oncogene-induced replication stress (RS) is a known source of endogenous DNA damage in cancer, which is suppressed by ATR and CHK1 kinases. We here show that ES suffer from high endogenous levels of RS, rendering them particularly dependent on the ATR pathway. Accordingly, two independent ATR inhibitors show in vitro toxicity in ES cell lines as well as in vivo efficacy in ES xenografts as single agents...
August 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27524497/pold3-is-haploinsufficient-for-dna-replication-in-mice
#5
Matilde Murga, Emilio Lecona, Irene Kamileri, Marcos Díaz, Natalia Lugli, Sotirios K Sotiriou, Marta E Anton, Juan Méndez, Thanos D Halazonetis, Oscar Fernandez-Capetillo
The Pold3 gene encodes a subunit of the Polδ DNA polymerase complex. Pold3 orthologs are not essential in Saccharomyces cerevisiae or chicken DT40 cells, but the Schizosaccharomyces pombe ortholog is essential. POLD3 also has a specialized role in the repair of broken replication forks, suggesting that POLD3 activity could be particularly relevant for cancer cells enduring high levels of DNA replication stress. We report here that POLD3 is essential for mouse development and is also required for viability in adult animals...
September 1, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27443740/replication-fork-stability-confers-chemoresistance-in-brca-deficient-cells
#6
Arnab Ray Chaudhuri, Elsa Callen, Xia Ding, Ewa Gogola, Alexandra A Duarte, Ji-Eun Lee, Nancy Wong, Vanessa Lafarga, Jennifer A Calvo, Nicholas J Panzarino, Sam John, Amanda Day, Anna Vidal Crespo, Binghui Shen, Linda M Starnes, Julian R de Ruiter, Jeremy A Daniel, Panagiotis A Konstantinopoulos, David Cortez, Sharon B Cantor, Oscar Fernandez-Capetillo, Kai Ge, Jos Jonkers, Sven Rottenberg, Shyam K Sharan, André Nussenzweig
Cells deficient in the Brca1 and Brca2 genes have reduced capacity to repair DNA double-strand breaks by homologous recombination and consequently are hypersensitive to DNA-damaging agents, including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein, PTIP, protects Brca1/2-deficient cells from DNA damage and rescues the lethality of Brca2-deficient embryonic stem cells. However, PTIP deficiency does not restore homologous recombination activity at double-strand breaks...
July 20, 2016: Nature
https://www.readbyqxmd.com/read/27067599/a-genome-wide-crispr-screen-identifies-cdc25a-as-a-determinant-of-sensitivity-to-atr-inhibitors
#7
Sergio Ruiz, Cristina Mayor-Ruiz, Vanesa Lafarga, Matilde Murga, Maria Vega-Sendino, Sagrario Ortega, Oscar Fernandez-Capetillo
One recurring theme in drug development is to exploit synthetic lethal properties as means to preferentially damage the DNA of cancer cells. We and others have previously developed inhibitors of the ATR kinase, shown to be particularly genotoxic for cells expressing certain oncogenes. In contrast, the mechanisms of resistance to ATR inhibitors remain unexplored. We report here on a genome-wide CRISPR-Cas9 screen that identified CDC25A as a major determinant of sensitivity to ATR inhibition. CDC25A-deficient cells resist high doses of ATR inhibitors, which we show is due to their failure to prematurely enter mitosis in response to the drugs...
April 21, 2016: Molecular Cell
https://www.readbyqxmd.com/read/26950370/usp7-is-a-sumo-deubiquitinase-essential-for-dna-replication
#8
Emilio Lecona, Sara Rodriguez-Acebes, Julia Specks, Andres J Lopez-Contreras, Isabel Ruppen, Matilde Murga, Javier Muñoz, Juan Mendez, Oscar Fernandez-Capetillo
Post-translational modification of proteins by ubiquitin (Ub) and Ub-like modifiers regulates DNA replication. We have previously shown that chromatin around replisomes is rich in SUMO and poor in Ub, whereas mature chromatin exhibits an opposite pattern. How this SUMO-rich, Ub-poor environment is maintained at sites of DNA replication in mammalian cells remains unexplored. Here we identify USP7 as a replisome-enriched SUMO deubiquitinase that is essential for DNA replication. By acting on SUMO and SUMOylated proteins, USP7 counteracts their ubiquitination...
April 2016: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/26550804/reducing-genomic-instability-in-ipscs
#9
EDITORIAL
Sergio Ruiz, Oscar Fernandez-Capetillo
No abstract text is available yet for this article.
October 27, 2015: Oncotarget
https://www.readbyqxmd.com/read/26456157/replication-stress-caused-by-low-mcm-expression-limits-fetal-erythropoiesis-and-hematopoietic-stem-cell-functionality
#10
Silvia Alvarez, Marcos Díaz, Johanna Flach, Sara Rodriguez-Acebes, Andrés J López-Contreras, Dolores Martínez, Marta Cañamero, Oscar Fernández-Capetillo, Joan Isern, Emmanuelle Passegué, Juan Méndez
Replicative stress during embryonic development influences ageing and predisposition to disease in adults. A protective mechanism against replicative stress is provided by the licensing of thousands of origins in G1 that are not necessarily activated in the subsequent S-phase. These 'dormant' origins provide a backup in the presence of stalled forks and may confer flexibility to the replication program in specific cell types during differentiation, a role that has remained unexplored. Here we show, using a mouse strain with hypomorphic expression of the origin licensing factor mini-chromosome maintenance (MCM)3 that limiting origin licensing in vivo affects the functionality of hematopoietic stem cells and the differentiation of rapidly-dividing erythrocyte precursors...
October 12, 2015: Nature Communications
https://www.readbyqxmd.com/read/26443207/nsmce2-suppresses-cancer-and-aging-in-mice-independently-of-its-sumo-ligase-activity
#11
Ariana Jacome, Paula Gutierrez-Martinez, Federica Schiavoni, Enrico Tenaglia, Paula Martinez, Sara Rodríguez-Acebes, Emilio Lecona, Matilde Murga, Juan Méndez, Maria A Blasco, Oscar Fernandez-Capetillo
The SMC5/6 complex is the least understood of SMC complexes. In yeast, smc5/6 mutants phenocopy mutations in sgs1, the BLM ortholog that is deficient in Bloom's syndrome (BS). We here show that NSMCE2 (Mms21, in Saccharomyces cerevisiae), an essential SUMO ligase of the SMC5/6 complex, suppresses cancer and aging in mice. Surprisingly, a mutation that compromises NSMCE2-dependent SUMOylation does not have a detectable impact on murine lifespan. In contrast, NSMCE2 deletion in adult mice leads to pathologies resembling those found in patients of BS...
November 3, 2015: EMBO Journal
https://www.readbyqxmd.com/read/26292731/limiting-replication-stress-during-somatic-cell-reprogramming-reduces-genomic-instability-in-induced-pluripotent-stem-cells
#12
Sergio Ruiz, Andres J Lopez-Contreras, Mathieu Gabut, Rosa M Marion, Paula Gutierrez-Martinez, Sabela Bua, Oscar Ramirez, Iñigo Olalde, Sara Rodrigo-Perez, Han Li, Tomas Marques-Bonet, Manuel Serrano, Maria A Blasco, Nizar N Batada, Oscar Fernandez-Capetillo
The generation of induced pluripotent stem cells (iPSC) from adult somatic cells is one of the most remarkable discoveries in recent decades. However, several works have reported evidence of genomic instability in iPSC, raising concerns on their biomedical use. The reasons behind the genomic instability observed in iPSC remain mostly unknown. Here we show that, similar to the phenomenon of oncogene-induced replication stress, the expression of reprogramming factors induces replication stress. Increasing the levels of the checkpoint kinase 1 (CHK1) reduces reprogramming-induced replication stress and increases the efficiency of iPSC generation...
August 21, 2015: Nature Communications
https://www.readbyqxmd.com/read/26077802/a-single-conserved-residue-mediates-binding-of-the-ribonucleotide-reductase-catalytic-subunit-rrm1-to-rrm2-and-is-essential-for-mouse-development
#13
Julia Specks, Emilio Lecona, Andrés J Lopez-Contreras, Oscar Fernandez-Capetillo
The ribonucleotide reductase (RNR) complex, composed of a catalytic subunit (RRM1) and a regulatory subunit (RRM2), is thought to be a rate-limiting enzymatic complex for the production of nucleotides. In humans, the Rrm1 gene lies at 11p15.5, a tumor suppressor region, and RRM1 expression in cancer has been shown to predict responses to chemotherapy. Nevertheless, whether RRM1 is essential in mammalian cells and what the effects of its haploinsufficiency are remain unknown. To model RNR function in mice we used a mutation previously described in Saccharomyces cerevisiae (Rnr1-W688G) which, despite being viable, leads to increased interaction of the RNR complex with its allosteric inhibitor Sml1...
September 1, 2015: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/25838540/increased-rrm2-gene-dosage-reduces-fragile-site-breakage-and-prolongs-survival-of-atr-mutant-mice
#14
Andres J Lopez-Contreras, Julia Specks, Jacqueline H Barlow, Chiara Ambrogio, Claus Desler, Svante Vikingsson, Sara Rodrigo-Perez, Henrik Green, Lene Juel Rasmussen, Matilde Murga, André Nussenzweig, Oscar Fernandez-Capetillo
In Saccharomyces cerevisiae, absence of the checkpoint kinase Mec1 (ATR) is viable upon mutations that increase the activity of the ribonucleotide reductase (RNR) complex. Whether this pathway is conserved in mammals remains unknown. Here we show that cells from mice carrying extra alleles of the RNR regulatory subunit RRM2 (Rrm2(TG)) present supraphysiological RNR activity and reduced chromosomal breakage at fragile sites. Moreover, increased Rrm2 gene dosage significantly extends the life span of ATR mutant mice...
April 1, 2015: Genes & Development
https://www.readbyqxmd.com/read/25636482/modeling-the-study-of-dna-damage-responses-in-mice
#15
REVIEW
Julia Specks, Maria Nieto-Soler, Andres J Lopez-Contreras, Oscar Fernandez-Capetillo
Damaged DNA has a profound impact on mammalian health and overall survival. In addition to being the source of mutations that initiate cancer, the accumulation of toxic amounts of DNA damage can cause severe developmental diseases and accelerate aging. Therefore, understanding how cells respond to DNA damage has become one of the most intense areas of biomedical research in the recent years. However, whereas most mechanistic studies derive from in vitro or in cellulo work, the impact of a given mutation on a living organism is largely unpredictable...
2015: Methods in Molecular Biology
https://www.readbyqxmd.com/read/25568916/hopes-for-the-year-ahead
#16
Óscar Fernández-Capetillo, Nieng Yan, Jen Dionne, Danielle Bassett, Suchitra Sebastian, Christine Hendon, Hilke Schlichting, Monya Baker
No abstract text is available yet for this article.
January 1, 2015: Nature
https://www.readbyqxmd.com/read/25513049/when-the-going-gets-tough-scientists-personal-challenges
#17
Claudia Lengerke, Oscar Fernandez-Capetillo, Iva Tolic-Norrelykke, Maria Barna, Todd Coleman, Dario Zamboni
No abstract text is available yet for this article.
October 9, 2014: Cell
https://www.readbyqxmd.com/read/25436265/when-the-going-gets-tough-scientists-personal-challenges
#18
Claudia Lengerke, Oscar Fernandez-Capetillo, Iva Tolic-Norrelykke, Maria Barna, Todd Coleman, Dario Zamboni
No abstract text is available yet for this article.
October 9, 2014: Cell
https://www.readbyqxmd.com/read/25257608/replication-stress-and-cancer-it-takes-two-to-tango
#19
REVIEW
Emilio Lecona, Oscar Fernández-Capetillo
Problems arising during DNA replication require the activation of the ATR-CHK1 pathway to ensure the stabilization and repair of the forks, and to prevent the entry into mitosis with unreplicated genomes. Whereas the pathway is essential at the cellular level, limiting its activity is particularly detrimental for some cancer cells. Here we review the links between replication stress (RS) and cancer, which provide a rationale for the use of ATR and Chk1 inhibitors in chemotherapy. First, we describe how the activation of oncogene-induced RS promotes genome rearrangements and chromosome instability, both of which could potentially fuel carcinogenesis...
November 15, 2014: Experimental Cell Research
https://www.readbyqxmd.com/read/25238193/the-maternal-side-of-fanconi-anemia
#20
COMMENT
Sergio Ruiz, Oscar Fernandez-Capetillo
Fanconi anemia is characterized by a higher sensitivity to DNA crosslinking agents, including aldehydes. In this issue of Molecular Cell, Oberbeck et al. (2014) reveal that detoxification of aldehydes by pregnant mothers contributes to limit the severity of the disease.
September 18, 2014: Molecular Cell
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