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1.
DNA is the hereditary material in humans and almost all other organisms. It is essential for maintaining accurate transmission of genetic information. In the life cycle, DNA replication, cell division, or genome damage, including that caused by endogenous and exogenous agents, may cause DNA aberrations. Of all forms of DNA damage, DNA double-strand breaks(DSBs) are the most serious. If the repair function is defective, DNA damage may cause gene mutation, genome instability, and cell chromosome loss, which in turn can even lead to tumorigenesis. DNA damage can be repaired through multiple mechanisms. Homologous recombination(HR) and non-homologous end joining(NHEJ) are the two main repair mechanisms for DNA DSBs. Increasing amounts of evidence reveal that protein modifications play an essential role in DNA damage repair.Protein deubiquitination is a vital post-translational modification which removes ubiquitin molecules or polyubiquitinated chains from substrates in order to reverse the ubiquitination reaction. This review discusses the role of deubiquitinating enzymes(DUBs) in repairing DNA DSBs. Exploring the molecular mechanisms of DUB regulation in DSB repair will provide new insights to combat human diseases and develop novel therapeutic approaches. 相似文献
2.
Maintenance of cellular homeostasis and genome integrity is a critical responsibility of DNA double-strand break(DSB)signaling.P53-binding protein 1(53BP1)plays a critical role in coordinating the DSB repair pathway choice and promotes the non-homologous end-joining(NHEJ)-mediated DSB repair pathway that rejoins DSB ends.New insights have been gained into a basic molecular mechanism that is involved in 53BP1 recruitment to the DNA lesion and how 53BP1 then recruits the DNA break-responsive effectors that promote NHEJ-mediated DSB repair while inhibiting homologous recombination(HR)signaling.This review focuses on the up-and downstream pathways of 53BP1 and how 53BP1 promotes NHEJ-mediated DSB repair,which in turn promotes the sensitivity of poly(ADP-ribose)polymerase inhibitor(PARPi)in BRCA1-deficient cancers and consequently provides an avenue for improving cancer therapy strategies. 相似文献
3.
Alkylated DNA lesions, induced by both exogenous chemical agents and endogenous metabolites, represent a major form of DNA damage in cells. The repair of alkylation damage is critical in all cells because such damage is cytotoxic and potentially mutagenic. Alkylation chemotherapy is a major therapeutic modality for many tumors, underscoring the importance of the repair pathways in cancer cells. Several different pathways exist for alkylation repair, including base excision and nucleotide excision repair, direct reversal by methyl-guanine methyltransferase(MGMT), and dealkylation by the AlkB homolog(ALKBH) protein family. However, maintaining a proper balance between these pathways is crucial for the favorable response of an organism to alkylating agents. Here, we summarize the progress in the field of DNA alkylation lesion repair and describe the implications for cancer chemotherapy. 相似文献
4.
Adenosine diphosphate(ADP)-ribosylation is a unique post-translational modification that regulates many biological processes,such as DNA damage repair.During DNA repair,ADP-ribosylation needs to be reversed by ADP-ribosylhydrolases.A group of ADP-ribosylhydrolases have a catalytic domain,namely the macrodomain,which is conserved in evolution from prokaryotes to humans.Not all macrodomains remove ADP-ribosylation.One set of macrodomains loses enzymatic activity and only binds to ADP-ribose(ADPR).Here,we summarize the biological functions of these macrodomains in DNA damage repair and compare the structure of enzymatically active and inactive macrodomains.Moreover,small molecular inhibitors have been developed that target macrodomains to suppress DNA damage repair and tumor growth.Macrodomain proteins are also expressed in pathogens,such as severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).However,these domains may not be directly involved in DNA damage repair in the hosts or pathogens.Instead,they play key roles in pathogen replication.Thus,by targeting macrodomains it may be possible to treat pathogen-induced diseases,such as coronavirus disease 2019(COVID-19). 相似文献
5.
Proteins are major functional units that are tightly connected to form complex and dynamic networks.These networks enable cells and organisms to operate properly and respond efficiently to environmental cues.Over the past decades,many biochemical methods have been developed to search for protein-binding partners in order to understand how protein networks are constructed and connected.At the same time,rapid development in proteomics and mass spectrometry(MS)techniques makes it possible to identify interacting proteins and build comprehensive protein-protein interaction networks.The resulting interactomes and networks have proven informative in the investigation of biological functions,such as in the field of DNA damage repair.In recent years,a number of proteins involved in DNA damage response and DNA repair pathways have been uncovered with MS-based protein-protein interaction studies.As the technologies for enriching associated proteins and MS become more sophisticated,the studies of protein-protein interactions are entering a new era.In this review,we summarize the strategies and recent developments for exploring protein-protein interaction.In addition,we discuss the application of these tools in the investigation of protein-protein interaction networks involved in DNA damage response and DNA repair. 相似文献
6.
USP11通过去泛素化p53调控p53稳定性 总被引：2，自引：0，他引：2
Jia-ying KE ;Cong-jie DAI ;Wen-lin WU ;Jin-hua GAO ;Ai-juan XIA ;Guang-ping LIU ;Kao-sheng LV ;Chun-lin WU 《Journal of Zhejiang University. Science. B》2014,15(12):1032-1038
研究目的：深入研究p53的泛素化及稳定性的调控。创新要点：发现一个新的调控p53去泛素化的酶USPll,它可以通过与p53的结合去泛素化并稳定p53,从而揭示了一个新的p53去泛素化调控的机制。研究方法：通过免疫共沉淀发现p53可以与USP11结合（图1a）,通过泛素化检测试验发现USPI1可以去泛素化p53（图3a和3b）,最后通过逆转录．聚合酶链式反应（RT—PCR）试验发现在DNA损伤后,USP11对p53转录活性的提高是非常重要的。 相似文献
7.
The 2015 Nobel Prize in Chemistry was awarded jointly to Tomas Lindahl, Paul Modrich and Aziz Sancar to honour their accomplishments in the field of DNA repair. Ever since the discovery of DNA structure and their importance in the storage of genetic information, questions about their stability became pertinent. A molecule which is crucial for the development and propagation of an organism must be closely monitored so that the genetic information is not corrupted. Thanks to the pioneering research work of Lindahl, Sancar, Modrich and their colleagues, we now have an holistic awareness of how DNA damage occurs and how the damage is rectified in bacteria as well as in higher organisms including human beings. A comprehensive understanding of DNA repair has proven crucial in the fight against cancer and other debilitating diseases. 相似文献
8.
DNA-damage response network at the crossroads of cell-cycle checkpoints,cellular senescence and apoptosis 总被引：2，自引：0，他引：2
Schmitt E Paquet C Beauchemin M Bertrand R 《Journal of Zhejiang University. Science. B》2007,8(6):377-397
Tissue homeostasis requires a carefully-orchestrated balance between cell proliferation, cellular senescence and cell death. Cells proliferate through a cell cycle that is tightly regulated by cyclin-dependent kinase activities. Cellular senescence is a safeguard program limiting the proliferative competence of cells in living organisms. Apoptosis eliminates unwanted cells by the coordinated activity of gene products that regulate and effect cell death. The intimate link between the cell cycle, cellular senescence, apoptosis regulation, cancer development and tumor responses to cancer treatment has become eminently apparent. Extensive research on tumor suppressor genes, oncogenes, the cell cycle and apoptosis regulatory genes has revealed how the DNA damage-sensing and -signaling pathways, referred to as the DNA-damage response network, are tied to cell proliferation, cell-cycle arrest, cellular senescence and apoptosis. DNA-damage responses are complex, involving ＂sensor＂ proteins that sense the damage, and transmit signals to ＂transducer＂ proteins, which, in turn, convey the signals to numerous ＂effector＂ proteins implicated in specific cellular pathways, including DNA repair mechanisms, cell-cycle checkpoints, cellular senescence and apoptosis. The Bcl-2 family of proteins stands among ＂the mos＂t crucial regula＂tors of apop＂tosis and performs vi＂tal func＂tions in deciding whether a cell will live or die after cancer chemotherapy and irradiation. In addition, several studies have now revealed that members of the Bcl-2 family also interface with the cell cycle, DNA repair/recombination and cellular senescence, effects that are generally distinct from their function in apoptosis. In this review, we report progress in understanding the molecular networks that regulate cell-cycle checkpoints, cellular senescence and apoptosis after DNA damage, and discuss the influence of some Bcl-2 family members on cell-cycle checkpoint regulation. 相似文献
9.
J E Richards 《Child development》1987,58(2):488-496
Infants were studied cross-sectionally at 14, 20, and 26 weeks of age. They were presented with varying and complex patterns on a TV screen. Two-thirds of the presentations were accompanied by an "interrupting stimulus" in the periphery delayed in time from the onset of fixation on the central stimulus. The infants were not easily distracted from looking at the central stimulus when the presentation of the interrupting stimulus occurred at the point of maximal heart rate (HR) deceleration. However, if the presentation occurred at the end of the HR response, the infants were easily distracted. Infants with large amounts of respiratory sinus arrhythmia (RSA; i.e., HR variability) in a baseline recording were less distractible during the deceleration-defined trials than were infants with low amounts of RSA. High-RSA infants also showed larger HR deceleration on these trials than did the low-RSA infants. These results are consistent with a model positing that sustained HR lowering during visual fixation is an index of active attention and that RSA is an index of voluntary, sustained attention in infants. 相似文献
10.
《信阳师范学院学报(哲学社会科学版)》2020,(2):44-51
受社会防卫本位和特殊预防理论决定,我国社区矫正形成了以人身危险性矫治和个别处遇为主导的教育矫正范式。然而,以教育矫正为核心理念的社区矫正机制忽视被害人(社区)的利益诉求和权利保障、社会公众的互动参与以及社会关系的修复,面对多元的矫治需求在实践中适用困难、效果有限。因此,经整合恢复性司法、被害人保护、社会复归、双面预防等前沿理论,形成以社会恢复为本位的社区矫正损害修复理论,将损害修复理念融入对犯罪人人格的矫正修复、被害人(社区)权益的补偿修复、社会规范的效力修复以及社会关系和秩序的整体修复之中,形成全方位、多层次、复合型的损害修复体系,并在此基础上构建损害修复型教育矫治模式的具体制度。 相似文献
11.
马云彤 《西安文理学院学报》2010,13(1):44-47
拓扑异构酶Ⅰ在DNA翻译和转录过程中催化单链DNA的断裂和连接,从而松弛DNA超螺旋,促进复制与转录的进行．拓扑异构酶Ⅰ抑制剂能够阻断DNA链的再连接,结果导致TopⅠ断裂复合物的积累,抑制复制和转录,造成DNA损伤,从而激活DNA损伤检验点,抑制细胞生长和诱发凋亡。喜树碱是最早发现、也是最重要和最广泛使用的拓扑异构酶Ⅰ抑制剂．细胞周期中DNA损伤、修复和检验点应答的分子机制是目前生命科学研究热点,而喜树碱已成为进行相关研究的重要的药理学工具． 相似文献
12.
Within the undergraduate mathematics curriculum, the topic of simple least-squares linear regression is often first encountered in multi-variable calculus where the line of best fit is obtained by using partial derivatives to find the slope and y-intercept of the line that minimizes the residual sum of squares. A markedly different approach from linear algebra, which could also be introduced in multi-variable calculus, obtains the regression line by vector projection. The latter viewpoint offers elegant proof of the equation relating the total, explained and unexplained variations. Consideration of data with the same regression line and correlation opens the door for a “mini-research experience” (MRE). A sequel MRE gives rise to an open Research Experience for Undergraduates topic to analyze reflection sequences and a fundamental connection between complex analysis and regression analysis. A few general guidelines and basic goals for MREs are included for those whose main interest is in undergraduate research. 相似文献
13.
跨损伤合成（translesion synthesis,TLS）是一种利用特殊的DNA聚合酶介导的修复过程,是细胞应答DNA损伤时的一种保守的耐受机制。由于TLS能使细胞耐受DNA损伤,降低肿瘤细胞对化疗药物或者放疗的敏感性,因此它可能是肿瘤产生耐药性或者辐射耐受性的潜在机制。通过靶向跨损伤合成通路,可提高包括神经胶质瘤在内的多种肿瘤患者的治疗疗效。 相似文献
14.
房琳 《商洛师范专科学校学报》2014,(2):35-39
城市路网路段修缮对路网运行造成重大影响。从对出行者通行时间影响的角度入手,结合交通均衡分配原则,提出路段修缮下用户出行时间损失指数,来度量路段修缮对路网运行效率的影响,给出路段修缮损失指数的算法。选取商州区局部城市路网,分别计算修缮路段彻底中断和单向通行时的路段修缮损失指数,进而对比说明不同情况下路段修缮对路网运行效率的不同影响。 相似文献
15.
Charlotte Larmuseau Jan Cornelis Luigi Lancieri Piet Desmet Fien Depaepe 《British journal of educational technology : journal of the Council for Educational Technology》2020,51(5):1548-1562
To have insight into cognitive load (CL) during online complex problem solving, this study aimed at measuring CL through physiological data. This study experimentally manipulated intrinsic and extraneous load of exercises in the domain of statistics, resulting in four conditions: high complex with hints, low complex with hints, high complex without hints and low complex without hints. The study had a within-subject-design in which 67 students solved the exercises in a randomized order. Self-reported CL was combined with physiological data, namely, galvanic skin response (GSR), skin temperature (ST), heart rate (HR) and heart rate variability (HRV). Multiple imputation was used for handling missing data from resp. 16 and 19 students for GSR/ST and HR/HRV. First, differences between conditions in view of physiological data were examined. Second, we investigated how much variance of self-reported CL and task performance was explained by physiological data. Finally, we investigated which features can be used to assess (objective) CL. Results revealed no significant differences between the manipulated conditions in terms of physiological data. Nonetheless, HR and ST were significantly related to self-reported CL, whereas ST to task performance. Additionally, this study revealed the potential of ST and HR to assess high CL. 相似文献
16.
Characterization of Pathogenic Human MSH2 Missense Mutations Using Yeast as a
Model System: A Laboratory Course in Molecular Biology 
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下载免费PDF全文 This work describes the project for an advanced undergraduate laboratory course in cell
and molecular biology. One objective of the course is to teach students a variety of
cellular and molecular techniques while conducting original research. A second objective
is to provide instruction in science writing and data presentation by requiring
comprehensive laboratory reports modeled on the primary literature. The project for the
course focuses on a gene, MSH2, implicated in the most common form of inherited colorectal
cancer. Msh2 is important for maintaining the fidelity of genetic material where it
functions as an important component of the DNA mismatch repair machinery. The goal of the
project has two parts. The first part is to create mapped missense mutation listed in the
human databases in the cognate yeast MSH2 gene and to assay for defects
in DNA mismatch repair. The second part of the course is directed towards understanding in
what way are the variant proteins defective for mismatch repair. Protein levels are
analyzed to determine if the missense alleles display decreased expression. Furthermore,
the students establish whether the Msh2p variants are properly localized to the nucleus
using indirect immunofluorescence and whether the altered proteins have lost their ability
to interact with other subunits of the MMR complex by creating recombinant DNA molecules
and employing the yeast 2-hybrid assay. 相似文献
17.
BackgroundCultural groups vary in how they understand child maltreatment and children's misbehavior and these cultural variations may impact the relationship between maltreatment and delinquency.ObjectiveThis study investigated the impact of maltreatment on delinquency among South Korean youth. Participants and Setting: Using Korean Children and Youth Panel Survey data, this study followed two cohorts of middle (n = 2,275) and high (n = 2,272) school youth for their first self-reported delinquency over 4 years.MethodDiscrete-time hazard model was used for the analyses.ResultsApproximately 19% of middle and 11% of high school youth engaged in delinquency for 4 years. Maltreatment is associated with delinquency only for high school youth (HR = 1.42). In both cohorts, male youth with high levels of aggression were more likely to engage in delinquency. Additional risk factors included high levels of depression (HR = 1.36) and negative attitudes toward school rules (HR = 0.68), father's education less than high school (HR = 0.63), low levels of self-control (HR = 0.63). Findings also identified culturally unique factors that place Korean youth at heightened risk of delinquency: mother's education more than high school (HR = 1.49) and higher family income (HR = 1.93).ConclusionPreventive interventions need to identify culturally specific risk factors for youth at increased risk of delinquency and thus these preventive interventions should be culturally tailored. 相似文献
18.
人力资源是企业最重要的资源之一,提高非人力资源经理的人力资源管理水平,已经成为改善企业管理水平的重要途径。在企业内部,人力资源管理工作很大程度上需要非人力资源经理及相关人员去实施,人力资源经理更多的是负责人力资源政策的制定与推行,而非人力资源经理作为人力资源的最终用户则更多地承担了人力资源管理的执行功能,双方应该是分工协作的关系,而且各有侧重。 相似文献
19.
吴访 《淮南职业技术学院学报》2004,4(4):33-35
指出知识经济时代人力资源开发与管理的重要意义，阐明了在知识经济时代人力资源开发与管理面临着由高科技引发的经济关系变化、信息化、提供驾驭全球竞争的高素质人才队伍以及科技创新等方面的挑战；论述了知识经济时代人力资源管理与开发的变革，包括：知识员工的管理、开发与管理的激励变革和网络化变革。 相似文献
20.
Waber DP Weiler MD Forbes PW Bernstein JH Bellinger DC Rappaport L 《Journal of learning disabilities》2003,36(5):467-483
We evaluated community general education (CGE; n = 178), community special education (CSE; n = 30) and hospital-referred (HR, n = 145) children (ages 7-6 to 11-11) prospectively over a 2-year period. During this period, 17 CGE children were referred for evaluation (community referred; CR). Prior to referral, CR children performed more poorly than community-nonreferred (CNR) children on cognitive ability, academic achievement, attention problems, and information processing. CR group performance was equivalent to that of CSE and HR groups, but HR children showed poorer academic achievement. Referred children performed more poorly on all measures than nonreferred, whether they met formal diagnostic criteria for a learning disorder or not. Learning disorders may be better conceptualized as a context-dependent problem of functional adaptation than as a disability analogous to physical disabilities, raising questions about the validity of using psychometric test scores as the criterion for identification. 相似文献