scholarly journals Role of some epigenetic factors in DNA damage response pathway

AIMS Genetics ◽  
2017 ◽  
Vol 4 (1) ◽  
pp. 69-83 ◽  
Author(s):  
Mrinalini Tiwari ◽  
◽  
Suhel Parvez ◽  
Paban K Agrawala
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Epigenetic Factors ◽  
Damage Response ◽  
Dna Damage Response Pathway

The Response to DNA Damage in CLL Cells Is Partly Determined by the Type of TP53 Mutation and Genomic Aberrations

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3119-3119
Author(s):  
Julia Mohr ◽  
Thorsten Zenz ◽  
Dirk Winkler ◽  
Andreas Bühler ◽  
Daniel Mertens ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Tp53 Mutation ◽  
Normal Karyotype ◽  
Type B ◽  
Tp53 Mutations ◽  
Damage Response ◽  
Dna Damage Response Pathway ◽  
11Q Deletion

Abstract A central role of the DNA damage response pathway and particularly p53 has been suggested by the prognostic role of 17p and 11q deletions in CLL. In the critical regions, two prominent genes are located that are involved in the cells’ response to DNA damage. Functional assessment of p53 may be of help to more precisely define a subgroup of patients with defects in the DNA damage response pathway. The most commonly used assays include FACS measurement of induction of p53/p21 after DNA damage, induction of p53 by nutlins or the measurement of transcriptional targets of p53 by RT-PCR or MLPA. The growing evidence of the impact of sole TP53 mutations on prognosis led us to analyse the DNA damage response in CLL with special focus on cases with TP53 mutations in the absence of 17p deletion. We investigated the response to gamma-irradiation (5Gy) in a cohort of 71 CLL cases. We enriched the cohort for the bad prognostic subgroups 17p-, 11q- and TP53 mutation in the absence of 17p deletion in order to precisely dissect the DNA damage response in these subgroups. Levels of p53 and p21 before and after treatment were determined by flow cytometry. Cells were additionally stained with a CD19 antibody to differentiate between CLL cells and CD19 negative cells (T-cells). We developed a strategy to normalize the median values of the CLL cells to the T-cells. Defects in the ATM/p53 pathway can be divided into type A and type B defects that are characterized by an impaired p21 induction and a high or a low basal p53 level, respectively (Pettitt et al. 2001). Basal p53 levels in 17p-cases (n=15) were significantly higher than for cases with TP53 mutation (P=0.012), 11q deletion (P<0.01) and normal karyotype/13p deletion (P<0.01), respectively). Furthermore, induction of p21 was impaired after irradiation compared to 11q del and normal/13q del (P=0.0066 and P=0.0002). In the cases with a sole TP53 mutation (n=10) we observed higher basal p53 levels compared to 11q- and normal/13q- cases (P=0.044 and P=0.007). The p21 response was heterogeneous, which may be partly explained by the presence of the mutation in subclones. Some cases with TP53 mutation (n=3) showed low p21 induction with low basal p53 levels resembling type B defects. This finding was explained by the presence of splice site and frameshift mutations that prevent formation of p53 protein. These findings suggest that not all cases with TP53 will exhibit the classical type A pattern of expression. A heterogeneous pattern of p21 induction was observed in patients with an 11q deletion (n=23) and in patients with normal karyotype or 13q deletion (n=23), the induction of 11q deleted cases being significantly lower (P=0.0102). Still, there were 11q deleted cases that responded normally to DNA damage (9/23). These cases can be hypothesized to have retained a functional ATM copy. Similarly, some of the cases with normal karyotype or 13q deletion showed impaired p21/p53 induction (n=6) and the cause for this impairment are under investigation. This study shows the importance of 17p deletions and TP53 mutations in altering the response to DNA damage in CLL. While this assay provides some insight into the functionality of the ATM/p53 pathway and the thus potentially the treatment response, the clinical and diagnostic value is currently unclear. We observed F-refractory cases showing a rather normal in vitro response to DNA damage. Along the same lines, cases with sole TP53 mutation are partly grouped with the type B defect, suggesting that TP53 mutations cannot be correctly grouped in all cases. Since the induction of p21 was not very strong, the use of other p53 targets could help to define different groups more precisely. Our findings suggest that the type of TP53 mutation will impact the DNA damage response and potentially lead to misclassification. In how far the heterogeneous pattern of 11q cases and some cases with low risk cytogenetics will help to differentiate biological and prognostic subgroups will need to be assessed in a large independent cohort with homogenous treatment. Induction of p21 and p53 in CLL with different genetic profile. Figure Figure

scholarly journals p53 Binding Protein 53BP1 Is Required for DNA Damage Responses and Tumor Suppression in Mice

2003 ◽  
Vol 23 (7) ◽  
pp. 2556-2563 ◽  
Author(s):  
Irene M. Ward ◽  
Kay Minn ◽  
Jan van Deursen ◽  
Junjie Chen
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Tumor Suppression ◽  
Binding Protein ◽  
Atm Kinase ◽  
Strand Breaks ◽  
Damage Response ◽  
Dna Strand ◽  
Dna Damage Response Pathway

ABSTRACT 53BP1 is a p53 binding protein of unknown function that binds to the central DNA-binding domain of p53. It relocates to the sites of DNA strand breaks in response to DNA damage and is a putative substrate of the ataxia telangiectasia-mutated (ATM) kinase. To study the biological role of 53BP1, we disrupted the 53BP1 gene in the mouse. We show that, similar to ATM−/− mice, 53BP1-deficient mice were growth retarded, immune deficient, radiation sensitive, and cancer prone. 53BP1−/− cells show a slight S-phase checkpoint defect and prolonged G2/M arrest after treatment with ionizing radiation. Moreover, 53BP1−/− cells feature a defective DNA damage response with impaired Chk2 activation. These data indicate that 53BP1 acts downstream of ATM and upstream of Chk2 in the DNA damage response pathway and is involved in tumor suppression.

Abstract 1774: Emerging role of Smad7 in DNA damage response pathway as a positive regulator.

2013 ◽  
Author(s):  
Sujin Park ◽  
Jin Muk Kang ◽  
Staci Jakyong Kim ◽  
Hyojung Kim ◽  
Seong-Jin Kim
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Positive Regulator ◽  
Damage Response ◽  
Dna Damage Response Pathway

scholarly journals Activation of the DNA Damage Response Pathway and the Role of NBS1 in Response to Hedgehog Signaling Inhibition

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
AKWASI AGYEMAN ◽  
Jennifer DeVecchio ◽  
TAPATI MAZUMDER ◽  
TING SHI ◽  
JANET HOUGHTON
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Hedgehog Signaling ◽  
Damage Response ◽  
Dna Damage Response Pathway

scholarly journals DNA Damage Response in Multiple Myeloma: The Role of the Tumor Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 504
Author(s):  
Takayuki Saitoh ◽  
Tsukasa Oda
Keyword(s):  
Multiple Myeloma ◽  
Dna Damage ◽  
Dna Repair ◽  
Tumor Microenvironment ◽  
Dna Damage Response ◽  
Genetic Instability ◽  
Dna Repair Mechanisms ◽  
Damage Response ◽  
Repair Mechanisms

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by genomic instability. MM cells present various forms of genetic instability, including chromosomal instability, microsatellite instability, and base-pair alterations, as well as changes in chromosome number. The tumor microenvironment and an abnormal DNA repair function affect genetic instability in this disease. In addition, states of the tumor microenvironment itself, such as inflammation and hypoxia, influence the DNA damage response, which includes DNA repair mechanisms, cell cycle checkpoints, and apoptotic pathways. Unrepaired DNA damage in tumor cells has been shown to exacerbate genomic instability and aberrant features that enable MM progression and drug resistance. This review provides an overview of the DNA repair pathways, with a special focus on their function in MM, and discusses the role of the tumor microenvironment in governing DNA repair mechanisms.

Dissecting the Role of Thyrotropin in the DNA Damage Response in Human Thyrocytes after 131I, γ Radiation and H2O2

2019 ◽  
Vol 105 (3) ◽  
pp. 839-853
Author(s):  
Aglaia Kyrilli ◽  
David Gacquer ◽  
Vincent Detours ◽  
Anne Lefort ◽  
Frédéric Libert ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Iodide Uptake ◽  
Transcriptomic Response ◽  
Uptake Inhibition ◽  
Γ Radiation ◽  
Damage Response

Abstract Background The early molecular events in human thyrocytes after 131I exposure have not yet been unravelled. Therefore, we investigated the role of TSH in the 131I-induced DNA damage response and gene expression in primary cultured human thyrocytes. Methods Following exposure of thyrocytes, in the presence or absence of TSH, to 131I (β radiation), γ radiation (3 Gy), and hydrogen peroxide (H2O2), we assessed DNA damage, proliferation, and cell-cycle status. We conducted RNA sequencing to profile gene expression after each type of exposure and evaluated the influence of TSH on each transcriptomic response. Results Overall, the thyrocyte responses following exposure to β or γ radiation and to H2O2 were similar. However, TSH increased 131I-induced DNA damage, an effect partially diminished after iodide uptake inhibition. Specifically, TSH increased the number of DNA double-strand breaks in nonexposed thyrocytes and thus predisposed them to greater damage following 131I exposure. This effect most likely occurred via Gα q cascade and a rise in intracellular reactive oxygen species (ROS) levels. β and γ radiation prolonged thyroid cell-cycle arrest to a similar extent without sign of apoptosis. The gene expression profiles of thyrocytes exposed to β/γ radiation or H2O2 were overlapping. Modulations in genes involved in inflammatory response, apoptosis, and proliferation were observed. TSH increased the number and intensity of modulation of differentially expressed genes after 131I exposure. Conclusions TSH specifically increased 131I-induced DNA damage probably via a rise in ROS levels and produced a more prominent transcriptomic response after exposure to 131I.

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