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Genois M.-M.,Chu Of Quebec Research Center | Genois M.-M.,Laval University | Masson J.-Y.,Chu Of Quebec Research Center | Masson J.-Y.,Laval University
PLoS Genetics | Year: 2014

Extrachromosomal DNA amplification is frequent in the protozoan parasite Leishmania selected for drug resistance. The extrachromosomal amplified DNA is either circular or linear, and is formed at the level of direct or inverted homologous repeated sequences that abound in the Leishmania genome. The RAD51 recombinase plays an important role in circular amplicons formation, but the mechanism by which linear amplicons are formed is unknown. We hypothesized that the Leishmania infantum DNA repair protein MRE11 is required for linear amplicons following rearrangements at the level of inverted repeats. The purified LiMRE11 protein showed both DNA binding and exonuclease activities. Inactivation of the LiMRE11 gene led to parasites with enhanced sensitivity to DNA damaging agents. The MRE11−/−parasites had a reduced capacity to form linear amplicons after drug selection, and the reintroduction of an MRE11 allele led to parasites regaining their capacity to generate linear amplicons, but only when MRE11 had an active nuclease activity. These results highlight a novel MRE11-dependent pathway used by Leishmania to amplify portions of its genome to respond to a changing environment. © 2014 Laffitte et al.


Genois M.-M.,Chu Of Quebec Research Center | Genois M.-M.,Laval University | Paquet E.R.,Chu Of Quebec Research Center | Paquet E.R.,Laval University | And 8 more authors.
Microbiology and Molecular Biology Reviews | Year: 2014

All living organisms are continuously faced with endogenous or exogenous stress conditions affecting genome stability. DNA repair pathways act as a defense mechanism, which is essential to maintain DNA integrity. There is much to learn about the regulation and functions of these mechanisms, not only inhumancells but also equally in divergent organisms. In trypanosomatids, DNA repair pathways protect the genome against mutations but also act as an adaptive mechanism to promote drug resistance. In this review, we scrutinize the molecular mechanisms and DNA repair pathways which are conserved in trypanosomatids. The recent advances made by the genome consortiums reveal the complete genomic sequences of several pathogens. Therefore, using bioinformatics and genomic sequences, we analyze the conservation of DNA repair proteins and their key protein motifs in trypanosomatids.Wethus present a comprehensive view of DNA repair processes in trypanosomatids at the crossroads of DNA repair and drug resistance. Copyright © 2014, American Society for Microbiology. All Rights Reserved.


Pauty J.,Chu Of Quebec Research Center | Pauty J.,Laval University | Rodrigue A.,Chu Of Quebec Research Center | Rodrigue A.,Laval University | And 5 more authors.
Biochemical Journal | Year: 2014

PALB2 [partner and localizer of BRCA2 (breast cancer earlyonset 1)] has emerged as a key player in the maintenance of genome integrity. Biallelic mutations in PALB2 cause FA (Fanconi's anaemia) subtype FA-N, a devastating inherited disorder marked by developmental abnormalities, bone marrow failure and childhood cancer susceptibility, whereas monoallelic mutations predispose to breast, ovarian and pancreatic cancer. The tumour suppressor role of PALB2 has been intimately linked to its ability to promote HR (homologous recombination)- mediated repair of DNA double-strand breaks. Because PALB2 lies at the crossroads between FA, HR and cancer susceptibility, understanding its function has become the primary focus of several studies. The present review discusses a current synthesis of the contribution of PALB2 to these pathways. We also provide a molecular description of FA- or cancer-associated PALB2 mutations. © 2014 Biochemical Society.


Gravel A.,Chu Of Quebec Research Center | Sinnett D.,University of Montréal | Flamand L.,Chu Of Quebec Research Center | Flamand L.,Laval University
PLoS ONE | Year: 2013

Introduction: Human herpesvirus 6 (HHV-6) is a ubiquitous pathogen infecting nearly 100% of the human population. Of these individuals, between 0.2% and 1% of them carry chromosomally-integrated HHV-6 (ciHHV-6). The biological consequences of chromosomal integration by HHV-6 remain unknown. Objective: To determine and compare the frequency of ciHHV-6 in children with acute lymphoblastic leukemia to healthy blood donors. Methodology: A total of 293 DNA samples from children with pre-B (n = 255), pre-pre-B (n = 4), pre-T (n = 26) and undetermined (n = 8) leukemia were analyzed for ciHHV-6 by quantitative TaqMan PCR (QPCR) using HHV-6 specific primers and probe. As control, DNA samples from 288 healthy individuals were used. Primers and probe specific to the cellular GAPDH gene were used to estimate integrity and DNA content. Results: Out of 293 DNA samples from the leukemic cohort, 287 contained amplifiable DNA. Of these, only 1 (0.35%) contained ciHHV-6. Variant typing indicates that the ci-HHV-6 corresponds to variant A. None of the 288 DNA samples from healthy individuals contained ciHHV-6. Conclusion: The frequency of ciHHV-6 in children with acute lymphoblastic leukemia is similar (p = 0.5) to that of healthy individuals. These results suggest that acute lymphoblastic leukemia does not originate as a consequence to integration of HHV-6 within the chromosomes. © 2013 Gravel et al.


Buisson R.,Chu Of Quebec Research Center | Buisson R.,Laval University | Buisson R.,Harvard University | Niraj J.,Chu Of Quebec Research Center | And 11 more authors.
Cell Reports | Year: 2014

One envisioned function of homologous recombination (HR) is to find a template for DNA synthesis from the resected 3'-OH molecules that occur during double-strand break (DSB) repair at collapsed replication forks. However, the interplay between DNA synthesis and HR remains poorly understood in higher eukaryotic cells. Here, we reveal functions for the breast cancer proteins BRCA2 and PALB2 at blocked replication forks and show a role for these proteins in stimulating polymerase η (Polη) to initiate DNA synthesis. PALB2, BRCA2, and Polη colocalize at stalled or collapsed replication forks after hydroxyurea treatment. Moreover, PALB2 and BRCA2 interact with Polη and are required to sustain the recruitment of Polη at blocked replication forks. PALB2 and BRCA2 stimulate Polη-dependent DNA synthesis on D loop substrates. We conclude that PALB2 and BRCA2, in addition to their functions in D loop formation, play crucial roles in the initiation of recombination-associated DNA synthesis by Polη-mediated DNA repair. © 2014 The Authors.


Ismail I.H.,University of Alberta | Ismail I.H.,Cairo University | Gagne J.-P.,Chu Of Quebec Research Center | Gagne J.-P.,Laval University | And 10 more authors.
Nature Cell Biology | Year: 2015

DNA double-strand breaks (DSBs) are repaired mainly by non-homologous end joining or homologous recombination (HR). Cell cycle stage and DNA end resection are believed to regulate the commitment to HR repair. Here we identify RNF138 as a ubiquitin E3 ligase that regulates the HR pathway. RNF138 is recruited to DNA damage sites through zinc fingers that have a strong preference for DNA with 5′- or 3′-single-stranded overhangs. RNF138 stimulates DNA end resection and promotes ATR-dependent signalling and DSB repair by HR, thereby contributing to cell survival on exposure to DSB-inducing agents. Finally, we establish that RNF138-dependent Ku removal from DNA breaks is one mechanism whereby RNF138 can promote HR. These results establish RNF138 as an important regulator of DSB repair pathway choice. © 2015 Macmillan Publishers Limited.


Flamand V.H.,Chu Of Quebec Research Center | Flamand V.H.,Laval University | Schneider C.,Chu Of Quebec Research Center | Schneider C.,Laval University
Archives of Physical Medicine and Rehabilitation | Year: 2014

Motor deficits in cerebral palsy disturb functional independence. This study tested whether noninvasive and painless repetitive peripheral magnetic stimulation could improve motor function in a 7-year-old boy with spastic hemiparetic cerebral palsy. Stimulation was applied over different nerves of the lower limbs for 5 sessions. We measured the concurrent aftereffects of this intervention on ankle motor control, gait (walking velocity, stride length, cadence, cycle duration), and function of brain motor pathways. We observed a decrease of ankle plantar flexors resistance to stretch, an increase of active dorsiflexion range of movement, and improvements of corticospinal control of ankle dorsiflexors. Joint mobility changes were still present 15 days after the end of stimulation, when all gait parameters were also improved. Resistance to stretch was still lower than prestimulation values 45 days after the end of stimulation. This case illustrates the sustained effects of repetitive peripheral magnetic stimulation on brain plasticity, motor function, and gait. It suggests a potential impact for physical rehabilitation in cerebral palsy. © 2014 American Congress of Rehabilitation Medicine.


Da Silva M.S.,Chu Of Quebec Research Center | Rudkowska I.,Chu Of Quebec Research Center
Molecular Nutrition and Food Research | Year: 2015

Dairy products contain milk fat, proteins, minerals, vitamin D, and other bioactive nutrients that have the potential to contribute to the association observed between increased dairy intake and a decreased risk of inflammation. The objective of this paper is to review the role of dairy bioactive molecules including dairy fat, proteins, micronutrients, and vitamins on inflammation markers in adipose, macrophage, and vascular tissues, which play a key role in the regulation of inflammation. A review was conducted to identify current scientific literature on dairy nutrients and inflammation in cell studies published until November 2014. The majority of saturated fatty acids (FAs) activate proinflammatory markers. Therefore, other dairy FAs or components may offset these harmful effects. Protein and amino acid composition of dairy products may have anti-inflammatory action. Magnesium may have beneficial effects on inflammatory profile; on the contrary, studies on vitamin D demonstrate conflicting results. In conclusion, numerous studies assessed the effects of individual or mixtures of FAs on inflammatory markers; yet, there is far less research on the effects of other dairy bioactive nutrients. The exact bioactive molecule or combination of these molecules in dairy products, which underlies the inverse association between dairy intake and inflammation remains to be elucidated. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Theriault S.,Chu Of Quebec Research Center
Obstetrics and gynecology | Year: 2013

To evaluate serum folate concentration early in pregnancy and any association with hypertensive disorders of pregnancy in a population exposed to folic acid supplementation and food fortification. This is a nested case-control study based on a prospective cohort of 7,929 pregnant women recruited in the Quebec City metropolitan area, including 214 participants who developed a hypertensive disorder of pregnancy and 428 normotensive participants in the control group matched for parity, multiple pregnancy, smoking status, gestational, and maternal age at inclusion, and duration of blood sample storage. Serum folate levels were measured at a mean of 14 weeks of gestation. More than 98% of the participants took folic acid or multivitamins before the end of the first trimester. Mean serum folate levels were accordingly high and there were no differences between women who further developed a hypertensive disorder of pregnancy compared with women in the control group (60.1 nmol/L compared with 57.9 nmol/L; P=.51). The proportion of participants with serum folate below the 10th percentile (less than 22.3 nmol/L) of age-matched women in our outpatient population was similar between groups (P=.66) and no participant had levels generally defined as folate deficiency (less than 10 nmol/L). In a general cohort of pregnant women benefiting from a national policy of folic acid food fortification combined with a high adherence to folic acid supplementation, serum folate levels are high and do not differ between women who develop a hypertensive disorder of pregnancy and women who remain normotensive. Further supplementation with higher doses is unlikely to be beneficial in such populations. II.


Da Silva M.S.,Chu Of Quebec Research Center | Rudkowska I.,Chu Of Quebec Research Center
Maturitas | Year: 2016

An antioxidant-rich diet has been shown to reduce the incidence of diet-induced metabolic diseases, such as obesity, diabetes and cardiovascular conditions, and contributes to healthy ageing. Yet, clinical trials investigating common dietary antioxidants, such as vitamins, have often failed to find a significant lowering effect on markers of oxidative stress. This review examines the latest clinical evidence on whether three novel potential antioxidant foods-fish omega-3 fatty acids, red wine and dairy products-can affect the oxidative status of healthy individuals. Clinical studies have reported heterogeneous results regarding the effect of fish oil, red wine and dairy products on oxidative stress. However, numerous studies have suggested that omega-3, red wine and dairy products may lower lipid peroxidation, a known trigger of cardiovascular disease, without affecting the oxidative status of healthy individuals. Overall, this review suggests that consumption of 1-2. g/day of omega-3, a moderate red wine intake (200-400. ml/day) or 2-3 portions/day of dairy products within a healthy diet exert beneficial effects on oxidative markers. Further investigation to ascertain these effects should focus on the antioxidant effects of long-term omega-3 supplementation, and of intake of dealcoholized red wine or higher dairy product consumption. © 2016 Elsevier Ireland Ltd.

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