scholarly journals Critical role of lysine 134 methylation on histone H2AX for γ-H2AX production and DNA repair

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Kenbun Sone ◽  
Lianhua Piao ◽  
Makoto Nakakido ◽  
Koji Ueda ◽  
Thomas Jenuwein ◽  
...  
Keyword(s):  
Dna Repair ◽  
Critical Role ◽  
Histone H2ax

scholarly journals Regulation of the cognitive aging process by the transcriptional repressor RP58

2021 ◽  
Author(s):  
Tomoko Tanaka ◽  
Shinobu Hirai ◽  
Hiroyuki Manabe ◽  
Kentaro Endo ◽  
Hiroko Shimbo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Knockout Mice ◽  
Cognitive Aging ◽  
Critical Role ◽  
Harmful Effect ◽  
Transcriptional Repressor ◽  
Repair Pathway ◽  
Wild Type

Aging involves a decline in physiology which is a natural event in all living organisms. An accumulation of DNA damage contributes to the progression of aging. DNA is continually damaged by exogenous sources and endogenous sources. If the DNA repair pathway operates normally, DNA damage is not life threatening. However, impairments of the DNA repair pathway may result in an accumulation of DNA damage, which has a harmful effect on health and causes an onset of pathology. RP58, a zinc-finger transcriptional repressor, plays a critical role in cerebral cortex formation. Recently, it has been reported that the expression level of RP58 decreases in the aged human cortex. Furthermore, the role of RP58 in DNA damage is inferred by the involvement of DNMT3, which acts as a co-repressor for RP58, in DNA damage. Therefore, RP58 may play a crucial role in the DNA damage associated with aging. In the present study, we investigated the role of RP58 in aging. We used RP58 hetero-knockout and wild-type mice in adolescence, adulthood, or old age. We performed immunohistochemistry to determine whether microglia and DNA damage markers responded to the decline in RP58 levels. Furthermore, we performed an object location test to measure cognitive function, which decline with age. We found that the wild-type mice showed an increase in single-stranded DNA and gamma-H2AX foci. These results indicate an increase in DNA damage or dysfunction of DNA repair mechanisms in the hippocampus as age-related changes. Furthermore, we found that, with advancing age, both the wild-type and hetero-knockout mice showed an impairment of spatial memory for the object and increase in reactive microglia in the hippocampus. However, the RP58 hetero-knockout mice showed these symptoms earlier than the wild-type mice did. These results suggest that a decline in RP58 level may lead to the progression of aging.

scholarly journals NR1D1 regulation by Ran GTPase via miR4472 identifies an essential vulnerability linked to aneuploidy in ovarian cancer

Oncogene ◽  
2021 ◽  
Author(s):  
Zied Boudhraa ◽  
Kossay Zaoui ◽  
Hubert Fleury ◽  
Maxime Cahuzac ◽  
Sophie Gilbert ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Critical Role ◽  
Inverse Correlation ◽  
Dna Damages ◽  
Ran Gtpase ◽  
Synthetic Lethal ◽  
Damage Repair ◽  
Repair Pathways

AbstractWhile aneuploidy is a main enabling characteristic of cancers, it also creates specific vulnerabilities. Here we demonstrate that Ran inhibition targets epithelial ovarian cancer (EOC) survival through its characteristic aneuploidy. We show that induction of aneuploidy in rare diploid EOC cell lines or normal cells renders them highly dependent on Ran. We also establish an inverse correlation between Ran and the tumor suppressor NR1D1 and reveal the critical role of Ran/NR1D1 axis in aneuploidy-associated endogenous DNA damage repair. Mechanistically, we show that Ran, through the maturation of miR4472, destabilizes the mRNA of NR1D1 impacting several DNA repair pathways. We showed that NR1D1 interacts with both PARP1 and BRCA1 leading to the inhibition of DNA repair. Concordantly, loss of Ran was associated with NR1D1 induction, accumulation of DNA damages, and lethality of aneuploid EOC cells. Our findings suggest a synthetic lethal strategy targeting aneuploid cells based on their dependency to Ran.

Biochemical control systems operating in the early hours of germination

1983 ◽  
Vol 61 (12) ◽  
pp. 3568-3577 ◽  
Author(s):  
Daphne J. Osborne
Keyword(s):  
Dna Repair ◽  
Nucleic Acids ◽  
Control Systems ◽  
Critical Role ◽  
Genetic Integrity ◽  
Biochemical Control

This review describes very early biochemical events during imbibition in seeds. It considers the control systems that regulate the production of nucleic acids and proteins when the dry seed first imbibes water. During the ageing of embryos in the dry state, DNA is progressively fragmented with an accumulation of single-stranded breaks. The critical role of DNA repair early in imbibition is considered in the context of genetic integrity of the nuclear template and successful germination.

scholarly journals Streptococcus pneumoniaesecretes hydrogen peroxide leading to DNA damage and apoptosis in lung cells

2015 ◽  
Vol 112 (26) ◽  
pp. E3421-E3430 ◽  
Author(s):  
Prashant Rai ◽  
Marcus Parrish ◽  
Ian Jun Jie Tay ◽  
Na Li ◽  
Shelley Ackerman ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Critical Role ◽  
Alveolar Epithelial Cells ◽  
Dna Double Strand Breaks ◽  
Histone H2ax ◽  
Alveolar Epithelial ◽  
Time Required ◽  
The Impact

Streptococcus pneumoniaeis a leading cause of pneumonia and one of the most common causes of death globally. The impact ofS. pneumoniaeon host molecular processes that lead to detrimental pulmonary consequences is not fully understood. Here, we show thatS. pneumoniaeinduces toxic DNA double-strand breaks (DSBs) in human alveolar epithelial cells, as indicated by ataxia telangiectasia mutated kinase (ATM)-dependent phosphorylation of histone H2AX and colocalization with p53-binding protein (53BP1). Furthermore, results show that DNA damage occurs in a bacterial contact-independent fashion and that Streptococcus pyruvate oxidase (SpxB), which enables synthesis of H2O2, plays a critical role in inducing DSBs. The extent of DNA damage correlates with the extent of apoptosis, and DNA damage precedes apoptosis, which is consistent with the time required for execution of apoptosis. Furthermore, addition of catalase, which neutralizes H2O2, greatly suppressesS. pneumoniae-induced DNA damage and apoptosis. Importantly,S. pneumoniaeinduces DSBs in the lungs of animals with acute pneumonia, and H2O2production byS. pneumoniaein vivo contributes to its genotoxicity and virulence. One of the major DSBs repair pathways is nonhomologous end joining for which Ku70/80 is essential for repair. We find that deficiency of Ku80 causes an increase in the levels of DSBs and apoptosis, underscoring the importance of DNA repair in preventingS. pneumoniae-induced genotoxicity. Taken together, this study shows thatS. pneumoniae-induced damage to the host cell genome exacerbates its toxicity and pathogenesis, making DNA repair a potentially important susceptibility factor in people who suffer from pneumonia.

scholarly journals Critical Role of Monoubiquitination of Histone H2AX Protein in Histone H2AX Phosphorylation and DNA Damage Response

2011 ◽  
Vol 286 (35) ◽  
pp. 30806-30815 ◽  
Author(s):  
Ching-Yuan Wu ◽  
Hong-Yo Kang ◽  
Wei-Lei Yang ◽  
Juan Wu ◽  
Yun Seong Jeong ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Critical Role ◽  
H2ax Phosphorylation ◽  
Histone H2ax ◽  
Damage Response ◽  
Histone H2ax Phosphorylation

scholarly journals XPC promotes MDM2-mediated degradation of the p53 tumor suppressor

2014 ◽  
Vol 25 (2) ◽  
pp. 213-221 ◽  
Author(s):  
Jing Yan Krzeszinski ◽  
Vitnary Choe ◽  
Jia Shao ◽  
Xin Bao ◽  
Haili Cheng ◽  
...  
Keyword(s):  
Dna Repair ◽  
Tumor Suppressor ◽  
Cancer Cells ◽  
Uv Irradiation ◽  
Binding Protein ◽  
P53 Protein ◽  
Critical Role ◽  
Direct Interaction ◽  
Degradation Pathway

Although ubiquitin receptor Rad23 has been implicated in bringing ubiquitylated p53 to the proteasome, how Rad23 recognizes p53 remains unclear. We demonstrate that XPC, a Rad23-binding protein, regulates p53 turnover. p53 protein in XPC-deficient cells remains ubiquitylated, but its association with the proteasome is drastically reduced, indicating that XPC regulates a postubiquitylation event. Furthermore, we found that XPC participates in the MDM2-mediated p53 degradation pathway via direct interaction with MDM2. XPC W690S pathogenic mutant is specifically defective for MDM2 binding and p53 degradation. p53 is known to become stabilized following UV irradiation but can be rendered unstable by XPC overexpression, underscoring a critical role of XPC in p53 regulation. Elucidation of the proteolytic role of XPC in cancer cells will help to unravel the detailed mechanisms underlying the coordination of DNA repair and proteolysis.

scholarly journals Role of Biomarkers in the Development of PARP Inhibitors

2016 ◽  
Vol 8s1 ◽  
pp. BIC.S36679 ◽  
Author(s):  
Bratati Ganguly ◽  
Sonia C. Dolfi ◽  
Lorna Rodriguez-Rodriguez ◽  
Shridar Ganesan ◽  
Kim M. Hirshfield
Keyword(s):  
Dna Repair ◽  
Critical Role ◽  
Parp Inhibitors ◽  
Resistance Mechanisms ◽  
Parp Inhibition ◽  
Technological Advances ◽  
Damage Repair ◽  
Selection For ◽  
Defective Dna Repair

Defects in DNA repair lead to genomic instability and play a critical role in cancer development. Understanding the process by which DNA damage repair is altered or bypassed in cancer may identify novel therapeutic targets and lead to improved patient outcomes. Poly(adenosine diphosphateribose) polymerase 1 (PARP1) has an important role in DNA repair, and novel therapeutics targeting PARP1 have been developed to treat cancers with defective DNA repair pathways. Despite treatment successes with PARP inhibitors (PARPi), intrinsic and acquired resistances have been observed. Preclinical studies and clinical trials in cancer suggest that combination therapy using PARPi and platinating agents is more effective than monotherapy in circumventing drug resistance mechanisms. Additionally, identification of biomarkers in response to PARPi will lead to improved patient selection for targeted cancer treatment. Recent technological advances have provided the necessary tools to examine many potential avenues to develop such biomarkers. This review examines the mechanistic rationale of PARP inhibition and potential biomarkers in their development for personalized therapy.

The Role of the SLP in Autism Spectrum Disorder Screening and Assessment

2008 ◽  
Vol 15 (2) ◽  
pp. 50-59 ◽  
Author(s):  
Amy Philofsky
Keyword(s):  
Language Development ◽  
Critical Role ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Children With Asd ◽  
Prevalence Estimates ◽  
Notable Increase ◽  
Screening Assessment ◽  
Critical Components

AbstractRecent prevalence estimates for autism have been alarming as a function of the notable increase. Speech-language pathologists play a critical role in screening, assessment and intervention for children with autism. This article reviews signs that may be indicative of autism at different stages of language development, and discusses the importance of several psychometric properties—sensitivity and specificity—in utilizing screening measures for children with autism. Critical components of assessment for children with autism are reviewed. This article concludes with examples of intervention targets for children with ASD at various levels of language development.

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