DNA repair

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Acute radiation dermatitis associated to polymorphisms in DNA repair genes

Acute radiation dermatitis associated to polymorphisms in DNA repair genes

Radiation therapy represents a primary line of treatment for several types of cancer. Despite the efforts on new technologies to minimize the damage to healthy tissue, adverse outcome in non-cancerous cells is common in a number of patients. Radiation dermatitis is one of the most frequent morbidity in patients undergoing radiation therapy and in severe cases it can interfere with the treatment outcome. Furthermore, growing evidence suggest that germ line polymorphisms could be associated with healthy tissue susceptibility to radiation therapy. We performed a candidate gene approach to study the relation between genes involved in DNA repair pathways and acute radiation dermatitis. Our results suggest an association between variants in genes OGG1 and APE1 from the base excision repair pathway and the onset of radiation dermatitis along with variables such as smoking habits and total dose delivered to the tumor. This is the first study that studies the genetic basis of this skin toxicity in a Latin American population and further studies with larger cohorts are required to validate this results.
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Are SNP-Smoking association studies needed in controls? DNA repair gene polymorphisms and smoking intensity

Are SNP-Smoking association studies needed in controls? DNA repair gene polymorphisms and smoking intensity

Smoking amount (PYS) may be causally associated with the most common alleles of XRCC3 Thr241Met and KLC3 Lys751Gln. In addition, smokers with the XRCC3 Thr241or KLC3 Lys751 alleles presented more nicotine addiction measured by FTND and more years smoking. There is evidence that XRCC1 Arg399Gln, KLC3 Lys751Gln and XRCC3 Thr241Met variants are functional [42,43]. Several authors have analysed the effect of different combinations of DNA repair SNPs and the levels of DNA adducts [43–47]. Inverse significant associations on DNA adducts have been detected in XRCC3 Met241Met carriers [46]. In the same way, other authors have also been described for XRCC3 Met241 carriers an association with reduced re- pair of X-ray-induced cytogenetic damage measured by chromatid aberrations [43,47]. The XRCC3 Thr241Met polymorphism is a non-conservative substitution with possible biological implications for the function of the enzyme and/or the interaction with others DNA repairing proteins. Amino acid variants in different domains of DNA repair proteins may not only affect different protein interactions, resulting in the expression of different phenotypes [48], but also the same polymorphism may have divergent effects on different DNA repair pathways and on different types of DNA damage [43].
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Polymorphisms in DNA-Repair Genes in a Cohort of Prostate Cancer Patients from Different Areas in Spain: Heterogeneity between Populations as a Confounding Factor in Association Studies.

Polymorphisms in DNA-Repair Genes in a Cohort of Prostate Cancer Patients from Different Areas in Spain: Heterogeneity between Populations as a Confounding Factor in Association Studies.

Radiation therapy (RT) is an effective treatment offered to patients with localized prostate cancer as a viable alternative to surgery [5]. Although both therapies showed comparable results in terms of survival [6], the main differences between them are related to adverse effects. Tumour control by RT requires the use of maximum dose that can be delivered while maintaining a tolerance risk of normal tissue toxicity, being clinical toxicity the factor limiting the efficacy of the treatment [7]. The role of genetics in the response of normal tissues to RT is widely accepted by the scientific community, and it would help to explain why patients treated with RT experience a large variation in normal tissue toxicity, even when similar doses and schedules are administered [8]. Radiation causes the loss of structure and function of most biologic molecules, including DNA. The individual DNA repair capacity consists of several mechanisms (nucleotide and base excision repair, homologous recombination, non-homologous endjoining, mismatch repair and telomere metabolism) and the individual capacity to repair damaged DNA may modify the response of tumour tissue and normal tissue to radiation [9]. Thus, studies of candidate genes have been focused on genes mainly involved in DNA damage recognition and repair (eg, ATM, XRCC1, XPD, ERCC1, LIG4, and TP53 among others), and also in free radical scavenging (eg, SOD2), or anti-inflammatory response (eg, TGFB1).
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Molecular mechanism involved in the mutagenicity induced by Aflatoxin B1Mecanismos moleculares involucrados en la mutagenicidad inducida por aflatoxina B1Mecanismos moleculares envolvidos na mutagenicidade induzida pela aflatoxina B1

Molecular mechanism involved in the mutagenicity induced by Aflatoxin B1Mecanismos moleculares involucrados en la mutagenicidad inducida por aflatoxina B1Mecanismos moleculares envolvidos na mutagenicidade induzida pela aflatoxina B1

subject Aflatoxin B1, Hepatitis B virus, Hepatocellular carcinoma, AFB1 metabolite, AFB1-DNA adducts, DNA repair.. subject aflatoxina B1, HBV, HCC, AFB1 metabolito, AFB1-DNA adutos, repa[r]

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Combinatorial antitumor effect of HDACs and the PI3K Akt mTOR pathway inhibition in a Pten deficient model of prostate cancer

Combinatorial antitumor effect of HDACs and the PI3K Akt mTOR pathway inhibition in a Pten deficient model of prostate cancer

Apoptosis induced by HDAC inhibition has been demonstrated to be dependent on AR expression [40]. Our study also demonstrates that PAN mediated apoptosis is AR dependent. PC3 cells response to PAN treatment was predominantly cell cycle arrest, whereas PC3- AR cells were significantly more sensitive to HDACi mediated apoptosis, as indicated by dramatic increases of cell membrane permeability, caspase activation and DNA fragmentation. The differential response to HDAC inhibition maybe explained by significant increase in DNA damage we observed in PC3-AR cells in response to HDACi. Transcription factors including AR are demonstrated to induce DNA damage via double strand breaks (DSBs) to mediate their transcriptional programs. These DSBs are recognized by DNA repair machinery such as poly (ADP-ribose) polymerase 1 (PARP1) and ATM. If not repaired properly, persistent DSBs can induce apoptosis [41]. We and others have shown that HDACi can mediate loss of AR transcriptional activity independent of AR degradation [12, 42], suggesting that cessation of AR transcription may also inhibit DNA damage repair, leading Figure 7: Schematic representation of activity of
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ADN daado y capacidad de reparacin en pacientes con neurofibromatosis tipo 1

ADN daado y capacidad de reparacin en pacientes con neurofibromatosis tipo 1

In that sense, DNA repair, a major mechanism for maintaining genome integrity and preventing muta- tions, has evolved into specific DNA repair pathways to repair different types of DNA damage, and to main- tain genomic integrity. In the human genome more than 130 genes have been found to be involved in these DNA repair systems [9, 10]. Thus, before launch- ing expensive and time-consuming genetics studies to identify these genetic modifiers, it is important to make sure that they really exist and that environmen- tal factors or other do not suffice to explain this phe- notypic variability. The idea that each neurofibroma would result from an independent somatic mutation event, regardless its origin from the same or different patient, was examined by Wiest et al. [26]. They per- formed a mutational screen of 33 neurofibromas from a mother and her daughter, both with NF1. Tumors from those two patients exhibited a high percentage of small mutations, and the authors proposed that functional variants of DNA repair genes modulate the frequency of second hits of the NF1 gene. Additional support for a role of DNA repair genes as modifiers in NF1 comes from the observation that mutations in DNA mismatch repair (MMR) genes, in the homozy- gous state, predispose individuals to NF1 [27, 28].
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Anàlisi de polimorfismes d’una sola base (SNPs) com a factors predictius de recaiguda en pacients amb càncer de pulmó de cèl•lula no petita quirúrgic

Anàlisi de polimorfismes d’una sola base (SNPs) com a factors predictius de recaiguda en pacients amb càncer de pulmó de cèl•lula no petita quirúrgic

An intact DNA repair mechanism reduces the accu- mulation of genetic aberrations that can contribute to the malignant potential of the tumor and to relapse af- ter treatment. It is known that ERCC1 expression levels can affect the outcome of lung cancer patients, even of those not receiving chemotherapy [38, 39]. A SNP in ERCC1 could modify the expression levels of the gene and thus affect its function. XPC and ERCC1 are involved sequentially in nucleotide excision repair. Whereas XPC is involved in damage recognition, ERCC1 cleaves the damaged DNA and removes the fragment containing the lesion [40]. In the present study, we found nearly significant differences in TTP according to the ERCC1 genotype, and in the multivar- iate analysis, the influence of ERCC1 rs735482 on OS reached significance. However, since the effect on OS in the univariate analysis was not statistically signifi- cant, we speculate that the influence of the ERCC1 SNP on OS is not independent of another variable. Var- ious SNPs have been identified within the gene ERCC1. To date, there has been no report on the influence of ERCC1 rs735482 on lung cancer risk; however, a SNP in exon 4 of ERCC1 has been associated with risk of lung cancer in a Caucasian population, although this
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The X ray repair cross complementing protein 1 (XRCC1) rs25487 polymorphism and susceptibility to cirrhosis in Brazilian patients with chronic viral hepatitis

The X ray repair cross complementing protein 1 (XRCC1) rs25487 polymorphism and susceptibility to cirrhosis in Brazilian patients with chronic viral hepatitis

However, few studies have investigated the influ- ence of polymorphisms in DNA repair genes in patients with viral hepatitis. In this pilot study, the possible influence of the XRCC1 rs25487 poly- morphism on the susceptibility to cirrhosis in viral hepatitis patients was investigated. Despite the small sample size, the results obtained are quite interest- ing and suggest that the XRCC1 rs25487 polymor- phism may play a role in the development of more aggressive diseases in these patients.

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5 Hydroxy 5 methylhydantoin DNA lesion, a molecular trap for DNA glycosylases

5 Hydroxy 5 methylhydantoin DNA lesion, a molecular trap for DNA glycosylases

as BER enzymes (61). Therefore, inhibitors of the Poly(ADP)ribose polymerase (a BER DNA repair enzyme), currently tested in the pre-clinical phase I, enhance the cytotoxic effects of ionizing radiation and DNA-damaging chemotherapy agents (62). More recently, signal interfering DNA (siDNA) technology proposed to use short modified DNA molecules [mimicking double-strand breaks (DSB)], to inhibit the DSB repair processes in cancer cells in association with radiotherapy or chemotherapy (63,64). Similarly, one can imagine that cHyd-containing oligonucleotides delivered to cancer cells will reduce the BER capacity by DNA glycosylase/AP lyase covalent trapping. Impairing the oxidized base removal thus potentiates the efficacy of anticancer drugs and radiotherapy. From this point of view, dL- and Oxa-containing DNA are also good candi- dates for this approach (Figure 9). The structural and functional determinants of DPC revealed by X-ray struc- tures provide a starting point for the rational design and synthesis of more efficient cHyd-derivatives. The future perspective of designing novel inhibitors rests on a better understanding of inhibition at the atomic level. With this aim in view, the crystal structures of Hyd-DPC formed with Nei structural family proteins are under investigation in our labs.
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Impact of NGS in the medical sciences: genetic syndromes with an increased risk of developing cancer as an example of the use of new technologies

Impact of NGS in the medical sciences: genetic syndromes with an increased risk of developing cancer as an example of the use of new technologies

(Nijmegen Breakage syndrome) plays an important role as a DNA DSB sensor and activator of ATM. The XP-proteins (Xeroderma Pigmentosum) are involved in nucleotide exci- sion repair as well as in transcription as chromatin remodel- ing factors. WRN (Werner syndrome) and BLM (Bloom syndrome) belong to the family of RecQ helicases; the for- mer plays multiple roles in DSB-repair, base excision re- pair, and telomere maintenance, while the latter is involved in damage recognition, homologous recombination, chro- mosome integrity, cell division, and chromatin remodeling. The genes involved in Fanconi anemia-pathway play a role in DNA repair, interstrand-crosslink repair and telomere maintenance (Knoch et al., 2012). Another developmental syndrome, Rothmund-Thomson syndrome, is also caused by mutations in a RecQ helicase (RECQL4), but it is not usually included in the breakage syndromes despite being one of its main differential diagnoses. Rothmund-Thomson syndrome is characterized by poikiloderma, telangiectasia, congenital skeletal abnormalities, premature aging, and in- creased risk of malignant disease, especially osteosarcoma.
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New Perspectives on Oxidized Genome Damage and Repair Inhibition by Pro-Oxidant Metals in Neurological Diseases

New Perspectives on Oxidized Genome Damage and Repair Inhibition by Pro-Oxidant Metals in Neurological Diseases

Despite an enormous increase in our understanding of the neuropathological events in aging and in ~200 types of neurological conditions, there is no cure available; current treatments slow progressive dementia only temporarily. This underscores the necessity of an overarching approach to explore newer strategies to unravel the mechanism of initiation/progression of neurodegeneration and to find more effective ways to prevent its onset, delay the progression and then effectively treat the disease to improve the quality of life for patients and their caregivers. Furthermore, despite multiple studies providing compelling evidence linking the misfolding/oligomerization of Aβ/tau, the build-up of Fe/Cu and other metals, the accumulation of genomic damage in the brain, how the interplay among these factors triggers neuronal apoptosis is still unclear. The role of metals as the key mediators of AD pathology has been reinforced by the fact that metal-chelation therapy has turned out to be promising in animal models of AD, although challenges regarding chelator choice and/or dosage together with the side effects of their sequestration of essential metals persist [9,190]. Our studies demonstrating that Fe/Cu acts as a ―double whammy‖ by inducing genome damage and also inhibiting its repair provided a molecular basis, whereby Cu reduces cysteine residues in NEILs, which could be reversed by a Cu chelator in combination with a reducing agent or curcumin, which has both chelating and reducing properties. In addition, other compounds/drugs, particularly of natural/plant origin with antioxidant/free radical scavenging, as well as metal chelation activities, should be looked into for their neuroprotective functions [191]. For example, melatonin, which possesses both antioxidant and metal chelation properties, has been demonstrated to reduce metal-induced toxicity in cells [192]. However, the protective role of melatonin in preventing metal-induced DNA repair inhibition still needs to be investigated. In view of melatonin’s ability to stimulate antioxidant enzymes, in addition to free radical scavenging and metal chelation, it will be interesting to examine a combination of melatonin and curcumin for preventing multimodal metal toxicity conditions. These results suggested that it is important to comprehensively understand the metal levels in a given case; characterizing the complete metal homeostasis and specific toxicity of the metals involved, including their role in genome damage/repair systems is required in order to develop an effective therapy [191]. This underscores the need to re-examine the role of metal toxicity in neurological diseases as a part of a therapeutic strategy in light of the new information of the human genome and its functions.
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Unidad didáctica: tecnología del DNA recombinante para la enseñanza de algunos conceptos en biología molecular

Unidad didáctica: tecnología del DNA recombinante para la enseñanza de algunos conceptos en biología molecular

Para el desarrollo del proyecto se establecieron cuatro fases: 1. Contextualización y antecedentes. Donde se realiza una revisión exhaustiva de distintas fuentes documentales en relación a la enseñanza de la Biología Molecular, trabajos prácticos relacionados con la tecnología del DNA recombinante, el contexto de Colombia y la UPN en relación a la biología molecular. Y una encuesta de pregunta abierta dirigida a estudiantes del ciclo de profundización de la Licenciatura en biología. 2. Diseño de la unidad didáctica; se plantean los contenidos a trabajar, objetivos, temáticas, y actividades tanto para la construcción de la unidad del estudiante como la del docente. 3. Validación, evaluación y ajustes, aquí se diseñan unos formatos de validación el cual se implementó al grupo de estudiantes, de la clase de introducción a la biotecnología, maestros y especialistas en el área, de la UPN. Los ajustes estuvieron sujetos a las recomendaciones, validación y evaluación de la unidad.
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DNA structure and replication

DNA structure and replication

DNA synthesis is completed, and the new DNA molecule assumes its double helix structure... Replication: Unwinding[r]

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BIOQ100  DNA estructura

BIOQ100 DNA estructura

¿QUE FORMA debe tener una molécula de DNA para que se puede determinar el tamaño por fraccionamiento electroforético en un gel de agarosa?.. Detección de secuencias especificas por h[r]

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Detección y genotipificación de Adenovirus en niños con gastroenteritis

Detección y genotipificación de Adenovirus en niños con gastroenteritis

El DNA extraído de las muestras positivas se sometió a una PCR para amplificar el gen hexón de adenovirus, se realizó una mezcla con un volumen final de 12.5 µI, utilizando PCR Master Mix (2x) (50 U/µ1 de Taq polimerasa DNA, 400 µM de dATP, 400 µM de dGTP, 400 µM de dCTP, 400 µM de dTTP, 3 mM MgCl2) (PROMEGA®) y oligonucleótidos específicos para genotipos 40 y 41 (Tabla 3), posteriormente se sometió en el termociclador a las siguientes condiciones: desnaturalización inicial a 94ºC por 4 min, seguido de 35 ciclos de 3 etapas a 94 ºC por 1 min, 57°C por 1 min y 72ºC por 2 min, finalmente un ciclo de 72ºC por 7 min (Verma y col., 2009). El producto obtenido se visualizó en gel de agarosa al 1. 5% , tras una corrida electroforética en buffer tris acetato EDTA (TAE) a 100 volts durante 35 min, teñido con SYBR® Safe (lnvitrogen), en exposición a luz ultravioleta en el transiluminador.
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Periimplantitis: Checkerboard DNA-DNA Hybridization Método para la Identificación de Bacterias Patógenas

Periimplantitis: Checkerboard DNA-DNA Hybridization Método para la Identificación de Bacterias Patógenas

The DNA Checkerboard hybridization technique has been used to comprehensively examine the microbial composition of supra and subgingival plaque in subjects in health and periodontitis, the salivary microbiota levels in relation to periodontal status, the relationship of cigarette smoking to the composition of the subgingival microbiota (Ximenez- Fyvie et al., 2000; Sakamoto et al ., 2005), the differences between the subgingival microbiota in subjects from different geographic locations, the relationship of ethnic/racial group, occupational and periodontal disease status, and effects of different periodontal therapies (Colombo et al., 1998; Ximenez- Fyvie et al., 2000). Recently, it was reported that this hybridization technique is useful for the enumeration of bacterial species in microbiologically complex systems. This technique is rapid, sensitive, and relatively inexpensive (Socransky et al., 1994).
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Diversidad genética, recombinación y filogeografía de bogomovirus que infectan tomate en Argentina

Diversidad genética, recombinación y filogeografía de bogomovirus que infectan tomate en Argentina

Hasta este momento, no se ha caracterizado el DNA-B del SbBMV. El DNA-A se caracterizó por primera vez a partir de una muestra de soja (Rodriguez Pardina et al., 2011). Aquí, se presentan dos secuencias de DNA-B [AR:Sa:Pichanal:Tom399:08:40-1] y [AR:Sa:Orán:Tom608:13:54-1] que no presentan altos porcentajes de identidad de secuencia con ningún otro DNA-B reportado. De la comparación de las secuencias de las regiones comunes se observó que comparten un 83 y 89% de identidad de secuencia respectivamente con las CRs del DNA-A de SbBMV. A pesar de que estos porcentajes no soy muy altos para la CR, dentro de esa región están exactamente los mismos iterones (AGGGG) por lo que estas secuencias son propuestas como el DNA-B probable de la especie SbBMV. Sumado a esto el agrupamiento por métodos de distancia genética realizado indica que las dos secuencias de CR del DNA-B agrupan con la CR de DNA-A del SbBMV. Desde un punto de vista biológico solo resta clonar el DNA-A del SbBMV de la misma muestra de la cual se obtuvo el DNA-B y realizar ensayos de infectividad para determinar los síntomas en tomate en una verdadera infección simple. Todas estas evidencias sugieren que existe una especie putativa muy relacionada al SbBMV de la cual no se ha caracterizado el DNA-A o estas dos secuencias constituyen el primer reporte del DNA-B del SbBMV.
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replicación

replicación

•La composición química de los ácidos nucleicos •La estructura 3D del DNA: naturaleza.. complementaria y antiparalela de la doble cadena del ácido desoxirribonucleico (DNA).[r]

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Tesis presentada a la Universidad Autónoma Metropolitana Unidad Iztapalapa para obtener el grado de Maestro en Biología Experimental

Tesis presentada a la Universidad Autónoma Metropolitana Unidad Iztapalapa para obtener el grado de Maestro en Biología Experimental

DNA e índice de proliferación; y de indicadores moleculares de inmortalización y transformación celular mediante identificación de la integración del DNA viral de l[r]

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Analisis de la region 5o de regulacion del Gen aprE de basillus subtilis

Analisis de la region 5o de regulacion del Gen aprE de basillus subtilis

Si en la regi6n de regulaci6n de aprE se forma una horquilla de DNA a traves de la uni6n de la protefna Hpr en sus sitios de uni6n al DNA y para la lormaci6n de esta horquilla se requier[r]

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