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      Ionizing radiation-induced DNA injury and damage detection in patients with breast cancer

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          Abstract

          Breast cancer is the most common malignancy in women. Radiotherapy is frequently used in patients with breast cancer, but some patients may be more susceptible to ionizing radiation, and increased exposure to radiation sources may be associated to radiation adverse events. This susceptibility may be related to deficiencies in DNA repair mechanisms that are activated after cell-radiation, which causes DNA damage, particularly DNA double strand breaks. Some of these genetic susceptibilities in DNA-repair mechanisms are implicated in the etiology of hereditary breast/ovarian cancer (pathologic mutations in the BRCA 1 and 2 genes), but other less penetrant variants in genes involved in sporadic breast cancer have been described. These same genetic susceptibilities may be involved in negative radiotherapeutic outcomes. For these reasons, it is necessary to implement methods for detecting patients who are susceptible to radiotherapy-related adverse events. This review discusses mechanisms of DNA damage and repair, genes related to these functions, and the diagnosis methods designed and under research for detection of breast cancer patients with increased radiosensitivity.

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          Most cited references107

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          γ-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin

          DNA double-strand breaks (DSBs) are extremely dangerous lesions with severe consequences for cell survival and the maintenance of genomic stability. In higher eukaryotic cells, DSBs in chromatin promptly initiate the phosphorylation of the histone H2A variant, H2AX, at Serine 139 to generate γ-H2AX. This phosphorylation event requires the activation of the phosphatidylinositol-3-OH-kinase-like family of protein kinases, DNA-PKcs, ATM, and ATR, and serves as a landing pad for the accumulation and retention of the central components of the signaling cascade initiated by DNA damage. Regions in chromatin with γ-H2AX are conveniently detected by immunofluorescence microscopy and serve as beacons of DSBs. This has allowed the development of an assay that has proved particularly useful in the molecular analysis of the processing of DSBs. Here, we first review the role of γ-H2AX in DNA damage response in the context of chromatin and discuss subsequently the use of this modification as a surrogate marker for mechanistic studies of DSB induction and processing. We conclude with a critical analysis of the strengths and weaknesses of the approach and present some interesting applications of the resulting methodology.
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            Homologous recombination and its regulation

            Homologous recombination (HR) is critical both for repairing DNA lesions in mitosis and for chromosomal pairing and exchange during meiosis. However, some forms of HR can also lead to undesirable DNA rearrangements. Multiple regulatory mechanisms have evolved to ensure that HR takes place at the right time, place and manner. Several of these impinge on the control of Rad51 nucleofilaments that play a central role in HR. Some factors promote the formation of these structures while others lead to their disassembly or the use of alternative repair pathways. In this article, we review these mechanisms in both mitotic and meiotic environments and in different eukaryotic taxa, with an emphasis on yeast and mammal systems. Since mutations in several proteins that regulate Rad51 nucleofilaments are associated with cancer and cancer-prone syndromes, we discuss how understanding their functions can lead to the development of better tools for cancer diagnosis and therapy.
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              Molecular views of recombination proteins and their control.

              The efficient repair of double-strand breaks in DNA is critical for the maintenance of genome stability and cell survival. Homologous recombination provides an efficient and faithful pathway of repair, especially in replicating cells, in which it plays a major role in tumour avoidance. Many of the enzymes that are involved in recombination have been isolated, and the details of this pathway are now being unravelled at the molecular level.
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                Author and article information

                Journal
                Genet Mol Biol
                Genet. Mol. Biol
                gmb
                Genetics and Molecular Biology
                Sociedade Brasileira de Genética
                1415-4757
                1678-4685
                Oct-Dec 2015
                Oct-Dec 2015
                : 38
                : 4
                : 420-432
                Affiliations
                [1 ]Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, Mexico
                [2 ]Centro de Investigación y Desarrollo en Ciencias de la Salud, Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, Mexico
                Author notes
                Send correspondence to Augusto Rojas-Martínez. Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Francisco I. Madero y Dr. Eduardo Aguirre Pequeño s/n, Colonia Mitras Centro, Monterrey, Nuevo León, Mexico. E-mail: arojasmtzgmail.com/augusto.rojasm@ 123456uanl.mx
                Article
                S1415-47572015005004104
                10.1590/S1415-475738420150019
                4763322
                26692152
                ff149440-10c3-44ef-8587-d586fa0c8fdd
                Copyright © 2015, Sociedade Brasileira de Genética.

                License information: This is an open-access article distributed under the terms of the Creative Commons Attribution License (type CC-BY), which permits unrestricted use, distribution and reproduction in any medium, provided the original article is properly cited.

                History
                : 19 January 2015
                : 15 July 2015
                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 99, Pages: 13
                Categories
                Review Articles

                Molecular biology
                breast cancer,ionizing radiation,dna damage,dna double strand break,dna repair analysis

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