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    • The other scenario pertaining to

    2020-06-29

    The other scenario pertaining to the significance of H2AX phosphorylation is based on the fact that the initiation of DNA fragmentation by CAD facilitates the chromatin condensation that occurs concurrently [15]. Apoptotic DNA fragmentation and chromatin condensation are important for the efficient clearing of genomic DNA and nucleosomes. This step in apoptosis, though not absolutely required for cell death, is very important in protecting the organism from auto-immmunization and oncogenic transformation [13], [14]. However, the molecular mechanisms underlying apoptotic chromatin condensation are still rather obscure. It has recently become increasingly clear that γH2AX plays a very important role in recruiting chromatin remodeling complexes and damage-responsive factors to the sites of DSBs [37], [38], [39], [40]. Therefore, it is quite plausible that H2AX phosphorylation may also facilitate apoptotic chromatin condensation to some extent by recruiting chromatin-modifying activities, i.e., factors involved in cleavage or condensation. Or else, it may simply promote the aggregation of nucleosomal fragments. The observed masking of the H2AX epitope in regions of chromatin condensation within the nucleus does indicate that γH2AX may be tightly complexed with other proteins. A similar function in apoptosis has been proposed for the phosphorylated version of histone H2B [35]. Apoptosis is an important factor in the response of cancerous AVE 0991 to chemotherapy or radiotherapy. However, acquired resistance towards apoptosis is a hallmark of most types of cancer and negatively affects the efficiency of chemotherapy [3]. Also, reversal of apoptosis can lead to tumor development such as those observed in therapy-related leukemia [75]. In the light of results described in this paper, it would be important to explore the significance of apoptotic H2AX phosphorylation in oncogenesis in future experiments.
    Acknowledgements
    Introduction Protecting its genome is paramount for each organism because DNA alterations such as mutations and chromosomal aberrations can lead to disease, tumorigenesis, or cell death [1]. A cell encounters a large number of DNA lesions each day that jeopardize the integrity of its genome, with the DNA double strand break (DSB) being the most toxic. The deleterious nature of DSBs is underscored by the fact that a single unrepaired DSB can cause cell death and misrepaired DSBs can result in chromosomal aberrations such as translocations and deletions, which can result in a loss of heterozygosity leading to genomic instability and subsequent malignant transformation. DSBs can be induced by a variety of means including intrinsic sources such as byproducts of cell metabolism and oxidative damage and extrinsic sources like ionizing radiation and chemotherapeutic agents [2], [3]. Although typically deleterious by nature, developing lymphocytes intentionally and systematically induce DSBs during V(D)J recombination and class switch recombination for the development of T and B cells [4]. To counter DSBs, organisms have developed a complex response that includes recognition of the broken DNA molecule, cellular signaling including modulation of the cell cycle, and ultimately repair of the DNA lesion [1], [5]. Two prominent pathways mediate the repair of DSBs in mammalian cells termed homologous recombination (HR) and non-homologous end-joining (NHEJ). HR mediates DSB repair by utilizing a homologous stretch of DNA to guide repair of the broken DNA strand. Since an easily accessible homologous template is found on a sister chromatid, HR is believed to be primarily active during the S and G2 phases of the cell cycle. As the name indicates, NHEJ mediates the direct re-ligation of the broken DNA molecule. Since NHEJ does not require a homologous template, it is not restricted to a particular phase of the cell cycle. It should be noted that homology independent repair in the absence of the canonical NHEJ factors also occurs. This alternative end-joining pathway (Alt-NHEJ), also named back-up NHEJ (B-NHEJ) and microhomology-mediated end-joining (MMEJ), is associated with DSB repair in which deletions occur at the repair junction and typically utilizes microhomologies distant from the DSB to mediate the repair [6]. In this review we will focus on the classical/canonical NHEJ pathway and hereafter “NHEJ” refers to this DSB repair pathway.