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      Susceptibility to DNA Damage as a Molecular Mechanism for Non-Syndromic Cleft Lip and Palate

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          Abstract

          Non-syndromic cleft lip/palate (NSCL/P) is a complex, frequent congenital malformation, determined by the interplay between genetic and environmental factors during embryonic development. Previous findings have appointed an aetiological overlap between NSCL/P and cancer, and alterations in similar biological pathways may underpin both conditions. Here, using a combination of transcriptomic profiling and functional approaches, we report that NSCL/P dental pulp stem cells exhibit dysregulation of a co-expressed gene network mainly associated with DNA double-strand break repair and cell cycle control (p = 2.88×10 −2–5.02×10 −9). This network included important genes for these cellular processes, such as BRCA1, RAD51, and MSH2, which are predicted to be regulated by transcription factor E2F1. Functional assays support these findings, revealing that NSCL/P cells accumulate DNA double-strand breaks upon exposure to H 2O 2. Furthermore, we show that E2f1, Brca1 and Rad51 are co-expressed in the developing embryonic orofacial primordia, and may act as a molecular hub playing a role in lip and palate morphogenesis. In conclusion, we show for the first time that cellular defences against DNA damage may take part in determining the susceptibility to NSCL/P. These results are in accordance with the hypothesis of aetiological overlap between this malformation and cancer, and suggest a new pathogenic mechanism for the disease.

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          Most cited references 71

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          Rank products: a simple, yet powerful, new method to detect differentially regulated genes in replicated microarray experiments.

          One of the main objectives in the analysis of microarray experiments is the identification of genes that are differentially expressed under two experimental conditions. This task is complicated by the noisiness of the data and the large number of genes that are examined simultaneously. Here, we present a novel technique for identifying differentially expressed genes that does not originate from a sophisticated statistical model but rather from an analysis of biological reasoning. The new technique, which is based on calculating rank products (RP) from replicate experiments, is fast and simple. At the same time, it provides a straightforward and statistically stringent way to determine the significance level for each gene and allows for the flexible control of the false-detection rate and familywise error rate in the multiple testing situation of a microarray experiment. We use the RP technique on three biological data sets and show that in each case it performs more reliably and consistently than the non-parametric t-test variant implemented in Tusher et al.'s significance analysis of microarrays (SAM). We also show that the RP results are reliable in highly noisy data. An analysis of the physiological function of the identified genes indicates that the RP approach is powerful for identifying biologically relevant expression changes. In addition, using RP can lead to a sharp reduction in the number of replicate experiments needed to obtain reproducible results.
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            Significance analysis of microar-rays applied to transcriptional responses to ionizing radiation

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              DNA double-strand break repair: from mechanistic understanding to cancer treatment.

              Accurate repair of DNA double-strand breaks is essential to life. Indeed, defective DNA double-strand break repair can lead to toxicity and large scale sequence rearrangements that cause cancer and promote premature aging. Here, we highlight the two major repair systems for handling DNA double-strand breaks: homologous recombination and non-homologous end joining. To clarify recombination mechanisms, we present animations that illustrate DNA strand movements. In addition to describing how these pathways operate, we also describe why appropriate pathway choice is critical to genomic stability, and we summarize key pathway control features related to cell cycle checkpoint and apoptosis signaling. Importantly, recent progress in delineating the effects of specific defects in repair and checkpoint control has helped to explain several disease phenotypes, including cancer and premature aging. Improved understanding of these pathways has also sparked development of novel chemotherapeutic strategies that kill tumors with increased specificity and efficacy. This review aims to provide a foundational understanding of how the homologous recombination and non-homologous end joining pathways operate, and to demonstrate how a better understanding of these processes has advanced both our understanding of the underlying causes of cancer and our ability to innovate novel cancer treatment strategies.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                12 June 2013
                : 8
                : 6
                Affiliations
                [1 ]Human Genome Research Center, Institute for Biosciences, University of São Paulo, São Paulo, Brazil
                [2 ]Dental Institute, Department of Craniofacial Development and Stem Cell Biology, King’s College London, London, United Kingdom
                [3 ]Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
                [4 ]SOBRAPAR Institute, Campinas, São Paulo, Brazil
                University of Miami, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: GSK LA DYS LCAL PFW CFM MRPB. Performed the experiments: GSK LA BVPA SGF AK PFW. Analyzed the data: GSK LA DYS PFW AK. Contributed reagents/materials/analysis tools: DFB CERA LCAL CFM. Wrote the paper: GSK LA PFW MRPB.

                Article
                PONE-D-13-00057
                10.1371/journal.pone.0065677
                3680497
                23776525

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 11
                Funding
                This work is funded by CNPq (National Counsel of Technological and Scientific Development), FAPESP (São Paulo Research Foundation), CAPES (Higher Education Co-Ordination Agency) and MCT (Ministry of Science, Technology and Innovation). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Biochemistry
                Nucleic Acids
                DNA
                DNA repair
                Developmental Biology
                Morphogenesis
                Birth Defects
                Stem Cells
                Genetics
                Molecular Genetics
                Gene Regulation
                Gene Expression
                Gene Networks
                Genetics of Disease
                Human Genetics

                Uncategorized

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