scholarly journals The role of NBS1 in the modulation of PIKK family proteins ATM and ATR in the cellular response to DNA damage

2006 ◽  
Vol 243 (1) ◽  
pp. 9-15 ◽  
Author(s):  
Junqing Zhou ◽  
Chang UK Lim ◽  
Jian Jian Li ◽  
Lu Cai ◽  
Ying Zhang
Keyword(s):  
Dna Damage ◽  
Cellular Response

Role of P53 Mutations in the Radiosensitivity Status of Tumor Cells

1998 ◽  
Vol 84 (5) ◽  
pp. 517-520 ◽  
Author(s):  
Vincenzo Chiarugi ◽  
Lucia Magnelli ◽  
Marina Cinelli
Keyword(s):  
Dna Damage ◽  
Cellular Response ◽  
P53 Protein ◽  
Cell Cycle Control ◽  
P53 Mutations ◽  
Wild Type ◽  
Bladder Tumors ◽  
Variable Effect ◽  
Wild Type P53

Wild-type p53 is involved in cellular response to DNA damage including cell cycle control, DNA repair and activation of apoptosis. Accumulation of p53 protein following DNA damage may initiate the apoptotic process, resulting in cell death. DNA damage induced by radiation is an example of apoptotic stimulus involving p53. Regulation of apoptosis by p53 can occur through transcriptional regulation of pro-apoptotic (e.g. bax) and anti-apoptotic (e.g. bel-2) factors. Although wild-type p53 usually sensitizes cells to radiation therapy, p53 mutations have a variable effect on radiation response. For example p53 mutations in bone or breast tumors have been found to be associated with resistance to chemotherapeutic drugs or ionizing radiation. Mutated p53 has has been reported to increase sensitivity to radiation and drugs in colorectal and bladder tumors. The present brief commentary tries to find an explanation at molecular level of these conflicting results.

scholarly journals The potential role of DFNA5, a hearing impairment gene, in p53-mediated cellular response to DNA damage

2006 ◽  
Vol 51 (8) ◽  
pp. 652-664 ◽  
Author(s):  
Yoshiko Masuda ◽  
Manabu Futamura ◽  
Hiroki Kamino ◽  
Yasuyuki Nakamura ◽  
Noriaki Kitamura ◽  
...  
Keyword(s):  
Dna Damage ◽  
Hearing Impairment ◽  
Cellular Response ◽  
Potential Role

scholarly journals Genomic Expression Responses to DNA-damaging Agents and the Regulatory Role of the Yeast ATR Homolog Mec1p

2001 ◽  
Vol 12 (10) ◽  
pp. 2987-3003 ◽  
Author(s):  
Audrey P. Gasch ◽  
Mingxia Huang ◽  
Sandra Metzner ◽  
David Botstein ◽  
Stephen J. Elledge ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Ionizing Radiation ◽  
Cellular Response ◽  
Expression Patterns ◽  
Wild Type ◽  
Data Set ◽  
Genomic Expression ◽  
Dna Damaging Agents

Eukaryotic cells respond to DNA damage by arresting the cell cycle and modulating gene expression to ensure efficient DNA repair. The human ATR kinase and its homolog in yeast, MEC1, play central roles in transducing the damage signal. To characterize the role of the Mec1 pathway in modulating the cellular response to DNA damage, we used DNA microarrays to observe genomic expression inSaccharomyces cerevisiae responding to two different DNA-damaging agents. We compared the genome-wide expression patterns of wild-type cells and mutants defective in Mec1 signaling, includingmec1, dun1, and crt1 mutants, under normal growth conditions and in response to the methylating-agent methylmethane sulfonate (MMS) and ionizing radiation. Here, we present a comparative analysis of wild-type and mutant cells responding to these DNA-damaging agents, and identify specific features of the gene expression responses that are dependent on the Mec1 pathway. Among the hundreds of genes whose expression was affected by Mec1p, one set of genes appears to represent an MEC1-dependent expression signature of DNA damage. Other aspects of the genomic responses were independent of Mec1p, and likely independent of DNA damage, suggesting the pleiotropic effects of MMS and ionizing radiation. The complete data set as well as supplemental materials is available at http://www-genome.stanford.edu/mec1 .

scholarly journals The role of FOXO3 in DNA damage response in thyrocytes

2011 ◽  
Vol 18 (5) ◽  
pp. 555-564 ◽  
Author(s):  
Antje Klagge ◽  
Carl Weidinger ◽  
Kerstin Krause ◽  
Beate Jessnitzer ◽  
Monika Gutknecht ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Cellular Response ◽  
Wild Type ◽  
Cycle Arrest ◽  
Damage Repair ◽  
Cell Clones ◽  
Human Wild Type

Members of the forkhead box-O (FOXO) transcription factors family play an important role in stress defence. FOXO3 deregulation has recently been identified as a hallmark of thyroid carcinogenesis. In this study, we explore the role of FOXO3 in defence of oxidative stress in normal thyrocytes. Stable rat thyroid cell lines were generated expressing either the human wild-type FOXO3, a constitutively activating FOXO3 mutant, or the empty control vector. Cell clones were characterised for proliferation, function and morphology. Hydrogen peroxide and UV irradiation were used to induce oxidative stress. Changes in FOXO3 activity, induction of cell cycle arrest or apoptosis and kinetics of DNA damage repair were analysed. Upregulation of FOXO3 in thyrocytes resulted in decreased proliferation and changes in morphology, but did not affect differentiation. Hydrogen peroxide stimulated the expression of the FOXO3 target genes growth arrest and DNA damage-inducible protein 45 α (Gadd45α) and Bcl-2 interacting mediator of cell death (BIM) and induced programmed cell death in cells with overexpression of the human wild-type FOXO3. In contrast, UV irradiation resulted in a distinct cellular response with activation of FOXO3-c-Jun-N-terminal kinase-Gadd45α signalling and induction of cell cycle arrest at the G2-M-checkpoint. This was accompanied by FOXO3-induced DNA damage repair as evidenced by lower DNA breaks over time in a comet assay in FOXO3 cell clones compared with control cells. In conclusion, FOXO3 is a pivotal relay in the coordination of the cellular response to genotoxic stress in the thyroid. Depending on the stimulus, FOXO3 induces either cell cycle arrest or apoptosis. Conversely, FOXO3 inactivation in thyroid cancers is consistent with genomic instability and loss of cell cycle control.

scholarly journals Cooperation of the Cockayne Syndrome Group B Protein and Poly(ADP-Ribose) Polymerase 1 in the Response to Oxidative Stress

2005 ◽  
Vol 25 (17) ◽  
pp. 7625-7636 ◽  
Author(s):  
Tina Thorslund ◽  
Cayetano von Kobbe ◽  
Jeanine A. Harrigan ◽  
Fred E. Indig ◽  
Mette Christiansen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cellular Response ◽  
Genetic Disorder ◽  
Cockayne Syndrome ◽  
Dna Lesions ◽  
Dna Breaks ◽  
Group B ◽  
Parp 1

ABSTRACT Cockayne syndrome (CS) is a rare genetic disorder characterized as a segmental premature-aging syndrome. The CS group B (CSB) protein has previously been implicated in transcription-coupled repair, transcriptional elongation, and restoration of RNA synthesis after DNA damage. Recently, evidence for a role of CSB in base excision repair of oxidative DNA lesions has accumulated. In our search to understand the molecular function of CSB in this process, we identify a physical and functional interaction between CSB and poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 is a nuclear enzyme that protects the integrity of the genome by responding to oxidative DNA damage and facilitating DNA repair. PARP-1 binds to single-strand DNA breaks which activate the catalytic ability of PARP-1 to add polymers of ADP-ribose to various proteins. We find that CSB is present at sites of activated PARP-1 after oxidative stress, identify CSB as a new substrate of PARP-1, and demonstrate that poly(ADP-ribosyl)ation of CSB inhibits its DNA-dependent ATPase activity. Furthermore, we find that CSB-deficient cell lines are hypersensitive to inhibition of PARP. Our results implicate CSB in the PARP-1 poly(ADP-ribosyl)ation response after oxidative stress and thus suggest a novel role of CSB in the cellular response to oxidative damage.

scholarly journals Sensing R-Loop-Associated DNA Damage to Safeguard Genome Stability

2021 ◽  
Vol 8 ◽  
Author(s):  
Carlo Rinaldi ◽  
Paolo Pizzul ◽  
Maria Pia Longhese ◽  
Diego Bonetti
Keyword(s):  
Dna Damage ◽  
Cellular Response ◽  
Genome Stability ◽  
Genome Instability ◽  
Hybrid Structure ◽  
Physiological Processes ◽  
Dna Strand ◽  
Template Dna ◽  
Dna Substrate

DNA transcription and replication are two essential physiological processes that can turn into a threat for genome integrity when they compete for the same DNA substrate. During transcription, the nascent RNA strongly binds the template DNA strand, leading to the formation of a peculiar RNA–DNA hybrid structure that displaces the non-template single-stranded DNA. This three-stranded nucleic acid transition is called R-loop. Although a programed formation of R-loops plays important physiological functions, these structures can turn into sources of DNA damage and genome instability when their homeostasis is altered. Indeed, both R-loop level and distribution in the genome are tightly controlled, and the list of factors involved in these regulatory mechanisms is continuously growing. Over the last years, our knowledge of R-loop homeostasis regulation (formation, stabilization, and resolution) has definitely increased. However, how R-loops affect genome stability and how the cellular response to their unscheduled formation is orchestrated are still not fully understood. In this review, we will report and discuss recent findings about these questions and we will focus on the role of ATM- and Rad3-related (ATR) and Ataxia–telangiectasia-mutated (ATM) kinases in the activation of an R-loop-dependent DNA damage response.

scholarly journals Role of the C Terminus of Mec1 Checkpoint Kinase in Its Localization to Sites of DNA Damage

2005 ◽  
Vol 16 (11) ◽  
pp. 5227-5235 ◽  
Author(s):  
Daisuke Nakada ◽  
Yukinori Hirano ◽  
Yuya Tanaka ◽  
Katsunori Sugimoto
Keyword(s):  
Dna Damage ◽  
Cellular Response ◽  
Protein A ◽  
Dna Lesions ◽  
Ataxia Telangiectasia Mutated ◽  
Dna Damage Signaling ◽  
C Terminus ◽  
Two Hybrid ◽  
Substitution Mutation

The large protein kinases, ataxia-telangiectasia mutated (ATM) and ATM-Rad3-related (ATR), coordinate the cellular response to DNA damage. In budding yeast, ATR homologue Mec1 plays a central role in DNA damage signaling. Mec1 interacts physically with Ddc2 and functions in the form of the Mec1–Ddc2 complex. To identify proteins interacting with the Mec1–Ddc2 complex, we performed a modified two-hybrid screen and isolated RFA1 and RFA2, genes that encode subunits of replication protein A (RPA). Using the two-hybrid system, we found that the extreme C-terminal region of Mec1 is critical for RPA binding. The C-terminal substitution mutation does not affect the Mec1–Ddc2 complex formation, but it does impair the interaction of Mec1 and Ddc2 with RPA as well as their association with DNA lesions. The C-terminal mutation also decreases Mec1 kinase activity. However, the Mec1 kinase-defect by itself does not perturb Mec1 association with sites of DNA damage. We also found that Mec1 and Ddc2 associate with sites of DNA damage in an interdependent manner. Our findings support the model in which Mec1 and Ddc2 localize to sites of DNA damage by interacting with RPA in the form of the Mec1–Ddc2 complex.

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