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DNA double-strand break signaling and human disorders
Toshiyuki Bohgaki, Miyuki Bohgaki, Razqallah Hakem
Genome Integrity , 2010, DOI: 10.1186/2041-9414-1-15
Abstract: Mammalian cells and organisms have evolved elegant ways to maintain their genomic integrity and respond to the various DNA lesions that they continuously face. DNA damage can result from exogenous stresses, such as ionizing radiation (IR), ultraviolet (UV) light and chemical compounds, or from endogenous insults such as reactive oxygen species (ROS) and DNA replication errors [1].DNA double-strand breaks (DSBs) are among the most serious and lethal types of DNA damage, as a single DSB is sufficient to kill a cell or disturb its genomic integrity [1]. DSBs are generated in response to exogenous and endogenous DNA insults. For instance, DSBs are induced in response to oncogenic activation [2]. In human precancerous lesions, oncogene activation has been shown to lead to continuous formation of DNA DSBs [3,4]. These DSBs activate the tumor suppressor p53 that mediate apoptosis and/or senescence to restrain the growth of the precancerous cells. In the presence of additional mutations that inactivate p53, precancerous cells become cancerous as they escape p53 mediated apoptosis and/or senescence [5,6]. In addition to the induced DSBs, there are also programmed DSBs that are critical for physiological processes such as meiosis and T and B-cell receptor rearrangements [7,8].DNA damage response (DDR) to various types of DNA insults is a well orchestrated process and is required to maintain genomic integrity (Figure 1) [9-12]. In response to DSBs, a signaling process activates cell cycle checkpoints and pauses cell cycle progression, thus granting time for damaged cells to repair their DNA (Figure 2 and section 2s) [13]. Two major repair pathways for DSBs exist in mammalian cells; the homologous recombination (HR) and the non-homologous end-joining (NHEJ) pathways [14]. The HR pathway is error free but requires an intact homologous template such as a sister chromatid. The NHEJ recombination pathway is the prominent pathway for DSB repair in mammalian cells; however this pathw
Genome Integrity - a new open access journal
Razqallah Hakem, M Prakash Hande, John Petrini, Predrag Slijepcevic
Genome Integrity , 2010, DOI: 10.1186/2041-9414-1-1
Abstract: By launching Genome Integrity, the first open access journal dedicated to the field of DNA damage response and associated processes, we aim to provide interested scientists with the journal that enables (i) immediate online access to articles as soon as they are accepted for publication and (ii) free and universal online access resulting in dissemination to the widest possible audience. We believe that the current lack of opportunities for immediate and free dissemination of articles focusing on the above area of research will make Genome Integrity a viable and competitive journal. We would like to note that Genome Integrity articles will be archived in PubMed [1] and all freely accessible full-text repositories. This complies with the policies of a number of funding bodies including the Wellcome Trust, NIH and Howard Hughes Medical Institute [2-5].The scope of Genome Integrity is wide and ambitious. We aim to attract articles focusing on all aspects of DNA damage response mechanisms, including mechanisms of DNA damage induction, sensing, signalling and repair, cell cycle check-point control, telomere maintenance and control of apoptosis. The journal also welcomes submissions which focus on mechanisms of chromosome stability maintenance and the effects of genotoxic stress on this stability. A growing area of research within the field is understanding DNA damage processing in the context of interphase nucleus chromatin and the journal certainly aims to attract authors interested in the mechanisms underlying these processes. Genome Integrity also intends to encourage publications from authors interested in exploring the effects of normal and pathological DNA damage responses on tissue homeostasis, cellular and organismal ageing and tumorigenesis in humans and in animal models. In brief, Genome Integrity will publish articles exploring fundamental, as well as translational, aspects of all processes behind DNA damage response, genome and chromosome stability maintenance
Synergistic Interaction of Rnf8 and p53 in the Protection against Genomic Instability and Tumorigenesis
Marie-Jo Halaby,Anne Hakem,Li Li,Samah El Ghamrasni,Shriram Venkatesan,Prakash M. Hande,Otto Sanchez,Razqallah Hakem
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003259
Abstract: Rnf8 is an E3 ubiquitin ligase that plays a key role in the DNA damage response as well as in the maintenance of telomeres and chromatin remodeling. Rnf8?/? mice exhibit developmental defects and increased susceptibility to tumorigenesis. We observed that levels of p53, a central regulator of the cellular response to DNA damage, increased in Rnf8?/? mice in a tissue- and cell type–specific manner. To investigate the role of the p53-pathway inactivation on the phenotype observed in Rnf8?/? mice, we have generated Rnf8?/?p53?/? mice. Double-knockout mice showed similar growth retardation defects and impaired class switch recombination compared to Rnf8?/? mice. In contrast, loss of p53 fully rescued the increased apoptosis and reduced number of thymocytes and splenocytes in Rnf8?/? mice. Similarly, the senescence phenotype of Rnf8?/? mouse embryonic fibroblasts was rescued in p53 null background. Rnf8?/?p53?/? cells displayed defective cell cycle checkpoints and DNA double-strand break repair. In addition, Rnf8?/?p53?/? mice had increased levels of genomic instability and a remarkably elevated tumor incidence compared to either Rnf8?/? or p53?/? mice. Altogether, the data in this study highlight the importance of p53-pathway activation upon loss of Rnf8, suggesting that Rnf8 and p53 functionally interact to protect against genomic instability and tumorigenesis.
Inactivation of Chk2 and Mus81 Leads to Impaired Lymphocytes Development, Reduced Genomic Instability, and Suppression of Cancer
Samah El Ghamrasni equal contributor,Ashwin Pamidi equal contributor,Marie Jo Halaby,Miyuki Bohgaki,Renato Cardoso,Li Li,Shriram Venkatesan,Swaminathan Sethu,Atsushi Hirao,Tak W. Mak,Manoor Prakash Hande,Anne Hakem ,Razqallah Hakem
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1001385
Abstract: Chk2 is an effector kinase important for the activation of cell cycle checkpoints, p53, and apoptosis in response to DNA damage. Mus81 is required for the restart of stalled replication forks and for genomic integrity. Mus81Δex3-4/Δex3-4 mice have increased cancer susceptibility that is exacerbated by p53 inactivation. In this study, we demonstrate that Chk2 inactivation impairs the development of Mus81Δex3-4/Δex3-4 lymphoid cells in a cell-autonomous manner. Importantly, in contrast to its predicted tumor suppressor function, loss of Chk2 promotes mitotic catastrophe and cell death, and it results in suppressed oncogenic transformation and tumor development in Mus81Δex3-4/Δex3-4 background. Thus, our data indicate that an important role for Chk2 is maintaining lymphocyte development and that dual inactivation of Chk2 and Mus81 remarkably inhibits cancer.
Genomic Instability, Defective Spermatogenesis, Immunodeficiency, and Cancer in a Mouse Model of the RIDDLE Syndrome
Toshiyuki Bohgaki equal contributor,Miyuki Bohgaki equal contributor,Renato Cardoso,Stephanie Panier,Dimphy Zeegers,Li Li,Grant S. Stewart,Otto Sanchez,M. Prakash Hande,Daniel Durocher,Anne Hakem ,Razqallah Hakem
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1001381
Abstract: Eukaryotic cells have evolved to use complex pathways for DNA damage signaling and repair to maintain genomic integrity. RNF168 is a novel E3 ligase that functions downstream of ATM,γ-H2A.X, MDC1, and RNF8. It has been shown to ubiquitylate histone H2A and to facilitate the recruitment of other DNA damage response proteins, including 53BP1, to sites of DNA break. In addition, RNF168 mutations have been causally linked to the human RIDDLE syndrome. In this study, we report that Rnf168?/? mice are immunodeficient and exhibit increased radiosensitivity. Rnf168?/? males suffer from impaired spermatogenesis in an age-dependent manner. Interestingly, in contrast to H2a.x?/?, Mdc1?/?, and Rnf8?/? cells, transient recruitment of 53bp1 to DNA double-strand breaks was abolished in Rnf168?/? cells. Remarkably, similar to 53bp1 inactivation, but different from H2a.x deficiency, inactivation of Rnf168 impairs long-range V(D)J recombination in thymocytes and results in long insertions at the class-switch junctions of B-cells. Loss of Rnf168 increases genomic instability and synergizes with p53 inactivation in promoting tumorigenesis. Our data reveal the important physiological functions of Rnf168 and support its role in both γ-H2a.x-Mdc1-Rnf8-dependent and -independent signaling pathways of DNA double-strand breaks. These results highlight a central role for RNF168 in the hierarchical network of DNA break signaling that maintains genomic integrity and suppresses cancer development in mammals.
Enslavement of Wireless Sensor Network to an RF Energy Harvesting System  [PDF]
Alex Mouapi, Nadir Hakem
Open Journal of Antennas and Propagation (OJAPr) , 2017, DOI: 10.4236/ojapr.2017.52006
Abstract: The abundance of telecommunications systems makes it possible to have somewhat significant quantity of radiofrequency energy in the environment. This energy can be recycled to power ultra-low-power devices such as Wireless Sensor Network (WSN). In this paper, the performance of a miniature RF/DC converter is evaluated in order to enslave a WSN’s per-formance to the amount of the recovered energy. More precisely, a highly sensitive and efficient rectifier is designed to achieve optimum performance in the GSM band. The design method relies on a judicious choice of the rectifying diode which is the basis of most losses in a rectifying antenna (rectenna). Optimum performance is achieved by using the gradient method search proposed in the Advanced Design System (ADS) software. A rectifier based on Schottky diodes HSMS 2850 used in a voltage doubler topology is thus obtained. A maximum RF/DC conversion efficiency of 36% is reached for an RF input power level of 10 dBm. An energy budget of a sensor node in a WSN having an equitable distribution of network loads is then defined and used to evaluate the performance of the WSN regarding the distance at which the Base Station (BS) can be located. The Low Energy Adaptive Clustering Hierarchy (LEACH) protocol is used for this purpose. The distance separating the WSN from the BS is used as the enslavement parameter. Our analysis shows that increasing the duration of each round results in an increase in the range of the WSN. As an example, a network with 100 nodes distributed over an area of may be located at 1.3 km from the base station when each node of the WSN must perform measurements every 1 min.
Neuronal Deletion of Caspase 8 Protects against Brain Injury in Mouse Models of Controlled Cortical Impact and Kainic Acid-Induced Excitotoxicity
Maryla Krajewska, Zerong You, Juan Rong, Christina Kress, Xianshu Huang, Jinsheng Yang, Tiffany Kyoda, Ricardo Leyva, Steven Banares, Yue Hu, Chia-Hung Sze, Michael J. Whalen, Leonardo Salmena, Razqallah Hakem, Brian P. Head, John C. Reed, Stan Krajewski
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024341
Abstract: Background Acute brain injury is an important health problem. Given the critical position of caspase 8 at the crossroads of cell death pathways, we generated a new viable mouse line (Ncasp8?/?), in which the gene encoding caspase 8 was selectively deleted in neurons by cre-lox system. Methodology/Principal Findings Caspase 8 deletion reduced rates of neuronal cell death in primary neuronal cultures and in whole brain organotypic coronal slice cultures prepared from 4 and 8 month old mice and cultivated up to 14 days in vitro. Treatments of cultures with recombinant murine TNFα (100 ng/ml) or TRAIL (250 ng/mL) plus cyclohexamide significantly protected neurons against cell death induced by these apoptosis-inducing ligands. A protective role of caspase 8 deletion in vivo was also demonstrated using a controlled cortical impact (CCI) model of traumatic brain injury (TBI) and seizure-induced brain injury caused by kainic acid (KA). Morphometric analyses were performed using digital imaging in conjunction with image analysis algorithms. By employing virtual images of hundreds of brain sections, we were able to perform quantitative morphometry of histological and immunohistochemical staining data in an unbiased manner. In the TBI model, homozygous deletion of caspase 8 resulted in reduced lesion volumes, improved post-injury motor performance, superior learning and memory retention, decreased apoptosis, diminished proteolytic processing of caspases and caspase substrates, and less neuronal degeneration, compared to wild type, homozygous cre, and caspase 8-floxed control mice. In the KA model, Ncasp8?/? mice demonstrated superior survival, reduced seizure severity, less apoptosis, and reduced caspase 3 processing. Uninjured aged knockout mice showed improved learning and memory, implicating a possible role for caspase 8 in cognitive decline with aging. Conclusions Neuron-specific deletion of caspase 8 reduces brain damage and improves post-traumatic functional outcomes, suggesting an important role for this caspase in pathophysiology of acute brain trauma.
Autonomous Wireless Sensors Network Based on Piezoelectric Energy Harvesting  [PDF]
Alex Mouapi, Nadir Hakem, Gilles Y. Delisle
Open Journal of Antennas and Propagation (OJAPr) , 2016, DOI: 10.4236/ojapr.2016.43011
Abstract: Wireless sensor networks (WSNs) offer an attractive solution to many environmental, security and process monitoring. However, their lifetime remains very limited by battery capacity. Through the use of piezoelectric energy harvesting techniques, ambient vibration can be captured and converted into usable electricity to create selfpowering WSN which is not limited by finite battery energy. This paper investigates analytically and experimentally the performance of a WSN powered by a Piezoelectric Energy Harvesting System (PEHS) and a material block-level modeling considering most key energy consumption of a wireless sensor node in a star topology network is proposed. By using real hardware parameters of existing components, the proposed model is used to evaluate the energetic budget of the node. The sensor node performance is evaluated regarding transmit packet size, duty cycle and the number of nodes that can be deployed. From the spectral properties of the available vibration inside two moving vehicles (automobile and train), the maximal recoverable power for each type of vehicle is estimated. Using a PEHS based on a cantilever beam optimized for low-frequency applications, 6 mW power is recovered in the case of the train while a 12.5 mW power is reached in the case of the automobile. It is observed that the sink may not operate with the recovered energy. However, the sensor node can sense and transmit data with a maximum size of 105.5 kbits when the duty cycle is 4 × 10-15. It is also achieved that the node is most effective when the measured physical phenomena vary slowly, such as the variations in temperature due to thermal inertia. Considering an optimized PEHS based on non-linear processing, it is shown that the sink can operate for 190% improvement of the recovered power.
60 GHz Polarization Reconfigurable DRA Antenna  [PDF]
Taieb Elkarkraoui, Gilles Y. Delisle, Nadir Hakem
Open Journal of Antennas and Propagation (OJAPr) , 2016, DOI: 10.4236/ojapr.2016.44014
Abstract: This paper outlines a new polarization reconfigurable EBG (Electromagnetic Band Gap) antenna in the 60 GHz millimeter waves band. The proposed hybrid antenna is composed of a multilayer pyramidal DRA (Dielectric Resonator Antenna) exciting source covered with a FSS (frequency Selective Surface) superstrate. The device can switch between circular and linear polarization by a simple 45° mechanical rotation of the pyramidal DRA. This structure has the advantage that it maintained stable bandwidth, gain, efficiency and radiation properties when switching between the two configurations of circular and linear polarization.
Role of Pirh2 in Mediating the Regulation of p53 and c-Myc
Anne Hakem ,Miyuki Bohgaki equal contributor,Bénédicte Lemmers equal contributor,Elisabeth Tai equal contributor,Leonardo Salmena,Elzbieta Matysiak-Zablocki,Yong-Sam Jung,Jana Karaskova,Lilia Kaustov,Shili Duan,Jason Madore,Paul Boutros,Yi Sheng,Marta Chesi,P. Leif Bergsagel,Bayardo Perez-Ordonez,Anne-Marie Mes-Masson,Linda Penn,Jeremy Squire,Xinbin Chen,Igor Jurisica,Cheryl Arrowsmith,Otto Sanchez,Samuel Benchimol,Razqallah Hakem
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002360
Abstract: Ubiquitylation is fundamental for the regulation of the stability and function of p53 and c-Myc. The E3 ligase Pirh2 has been reported to polyubiquitylate p53 and to mediate its proteasomal degradation. Here, using Pirh2 deficient mice, we report that Pirh2 is important for the in vivo regulation of p53 stability in response to DNA damage. We also demonstrate that c-Myc is a novel interacting protein for Pirh2 and that Pirh2 mediates its polyubiquitylation and proteolysis. Pirh2 mutant mice display elevated levels of c-Myc and are predisposed for plasma cell hyperplasia and tumorigenesis. Consistent with the role p53 plays in suppressing c-Myc-induced oncogenesis, its deficiency exacerbates tumorigenesis of Pirh2?/? mice. We also report that low expression of human PIRH2 in lung, ovarian, and breast cancers correlates with decreased patients' survival. Collectively, our data reveal the in vivo roles of Pirh2 in the regulation of p53 and c-Myc stability and support its role as a tumor suppressor.
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