Abstract B22: Combined disruption of ATM and CHK1 functionalities reveals redundancies in the DNA damage response pathways and results in synthetic growth inhibition following γ-irradiation

DNA damage evokes a complex and highly coordinated DNA damage response (DDR) that is integral to the suppression of genomic instability. Double-strand breaks (DSBs) are considered the most deleterious form damage. Evidence suggests that trimethylation of histone H3 lysine 9 (H3K9me3) presents a barrier to DSB repair. Also, global levels of histone methylation are clinically predictive for several tumor types. Therefore, demethylation of H3K9 may be an important step in the repair of DSBs. The KDM4 subfamily of demethylases removes H3K9 tri- and dimethylation and contributes to the regulation of cellular differentiation and proliferation; mutation or aberrant expression of KDM4 proteins has been identified in several human tumors. We hypothesize that members of the KDM4 subfamily may be components of the DDR. We found that Kdm4b-enhanced GFP (EGFP) and KDM4D-EGFP were recruited rapidly to DNA damage induced by laser micro-irradiation. Focusing on the clinically relevant Kdm4b, we found that recruitment was dependent on poly(ADP-ribose) polymerase 1 activity as well as Kdm4b demethylase activity. The Kdm4 proteins did not measurably accumulate at γ-irradiation-induced γH2AX foci. Nevertheless, increased levels of Kdm4b were associated with decreased numbers of γH2AX foci 6 h after irradiation as well as increased cell survival. Finally, we found that levels of H3K9me2 and H3K9me3 were decreased at early time points after 2 gray of γ-irradiation. Taken together, these data demonstrate that Kdm4b is a DDR protein and that overexpression of Kdm4b may contribute to the failure of anti-cancer therapy that relies on the induction of DNA damage.

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UHRF1 is a genome caretaker that facilitates the DNA damage response to γ-irradiation

Genome Integrity ◽

10.1186/2041-9414-1-7 ◽

2010 ◽

Vol 1 (1) ◽

pp. 7 ◽

Cited By ~ 20

Author(s):

Helena Mistry ◽

Laura Tamblyn ◽

Hussein Butt ◽

Daniel Sisgoreo ◽

Aileen Gracias ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Γ Irradiation ◽

A Genome ◽

Damage Response

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The histone demethylase LSD1/KDM1A promotes the DNA damage response

The Journal of Cell Biology ◽

10.1083/jcb.201302092 ◽

2013 ◽

Vol 203 (3) ◽

pp. 457-470 ◽

Cited By ~ 61

Author(s):

Nima Mosammaparast ◽

Haeyoung Kim ◽

Benoit Laurent ◽

Yu Zhao ◽

Hui Jun Lim ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Ubiquitin Ligase ◽

Histone Demethylase ◽

Dependent Manner ◽

Γ Irradiation ◽

Histone Demethylation ◽

Direct Role ◽

Damage Response ◽

Histone Ubiquitylation

Histone demethylation is known to regulate transcription, but its role in other processes is largely unknown. We report a role for the histone demethylase LSD1/KDM1A in the DNA damage response (DDR). We show that LSD1 is recruited directly to sites of DNA damage. H3K4 dimethylation, a major substrate for LSD1, is reduced at sites of DNA damage in an LSD1-dependent manner. The E3 ubiquitin ligase RNF168 physically interacts with LSD1 and we find this interaction to be important for LSD1 recruitment to DNA damage sites. Although loss of LSD1 did not affect the initial formation of pH2A.X foci, 53BP1 and BRCA1 complex recruitment were reduced upon LSD1 knockdown. Mechanistically, this was likely a result of compromised histone ubiquitylation preferentially in late S/G2. Consistent with a role in the DDR, knockdown of LSD1 resulted in moderate hypersensitivity to γ-irradiation and increased homologous recombination. Our findings uncover a direct role for LSD1 in the DDR and place LSD1 downstream of RNF168 in the DDR pathway.

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Activation of DNA damage response pathways in human mesenchymal stem cells exposed to cisplatin or γ-irradiation

Cell Cycle ◽

10.4161/cc.10.21.17972 ◽

2011 ◽

Vol 10 (21) ◽

pp. 3768-3777 ◽

Cited By ~ 48

Author(s):

Áine M. Prendergast ◽

Séverine Cruet-Hennequart ◽

Georgina Shaw ◽

Frank P. Barry ◽

Michael P. Carty

Keyword(s):

Stem Cells ◽

Dna Damage ◽

Mesenchymal Stem Cells ◽

Dna Damage Response ◽

Human Mesenchymal Stem Cells ◽

Γ Irradiation ◽

Damage Response

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Mice lacking NF-κB1 exhibit marked DNA damage responses and more severe gastric pathology in response to intraperitoneal tamoxifen administration

10.1101/112656 ◽

2017 ◽

Author(s):

Michael D Burkitt ◽

Jonathan M Williams ◽

Tristan Townsend ◽

Rachael Hough ◽

Carrie A Duckworth ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Cell Loss ◽

Gastric Atrophy ◽

Gastric Lesions ◽

Γ Irradiation ◽

Damage Response ◽

Gastric Corpus ◽

The Difference ◽

Epithelial Lesions

AbstractBackgroundTamoxifen (TAM) has recently been shown to cause acute gastric atrophy and metaplasia in mice. We have previously demonstrated that the outcome of Helicobacter felis infection, which induces similar gastric lesions in mice, is altered by deletion of specific NF-κB subunits. Nfkb1-/- mice developed more severe gastric atrophy than wild-type (WT) mice 6 weeks after H. felis infection. In contrast, Nfkb2-/- mice were protected from this pathology. We therefore hypothesized that gastric lesions induced by TAM may be similarly regulated by signaling via NF-κB subunits.MethodsGroups of 5 female C57BL/6 (WT), Nfkb1-/-, Nfkb2-/- and c-Rel-/- mice were administered 150mg/kg TAM by IP injection. 72 hours later, gastric corpus tissues were taken for quantitative histological assessment. In addition, groups of 6 female WT and Nfkb1-/- mice were exposed to 12Gy γ-irradiation. Gastric epithelial apoptosis was quantified 6 and 48 hours after irradiation.ResultsTAM induced gastric epithelial lesions in all strains of mice, but this was more severe in Nfkb1-/- mice than WT mice. Nfkb1-/- mice exhibited more severe parietal cell loss than WT mice, had increased gastric epithelial expression of Ki67 and had an exaggerated gastric epithelial DNA damage response as quantified by γH2AX. To determine investigate whether the difference in gastric epithelial DNA damage response of Nfkb1-/- mice was unique to TAM induced DNA damage, or a generic consequence of DNA damage, we also assessed gastric epithelial apoptosis following γ-irradiation. 6 hours after γ-irradiation, gastric epithelial apoptosis was increased in the gastric corpus and antrum of Nfkb1-/- mice.ConclusionsNF-κB1 mediated signaling regulates the development of gastric mucosal pathology following TAM administration. This is associated with an exaggerated gastric epithelial DNA damage response. This aberrant response appears to reflect a more generic sensitization of the gastric mucosa of Nfkb1-/- mice to DNA damage.

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The Plant DNA Damage Response: Signaling Pathways Leading to Growth Inhibition and Putative Role in Response to Stress Conditions

Frontiers in Plant Science ◽

10.3389/fpls.2019.00653 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 18

Author(s):

Maher-Un Nisa ◽

Ying Huang ◽

Moussa Benhamed ◽

Cécile Raynaud

Keyword(s):

Dna Damage ◽

Growth Inhibition ◽

Signaling Pathways ◽

Dna Damage Response ◽

Stress Conditions ◽

Plant Dna ◽

Putative Role ◽

Damage Response ◽

Response To Stress

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Tissue-specific DNA damage response in Mouse Whole-body irradiation

Molecular & Cellular Toxicology ◽

10.1007/s13273-021-00195-w ◽

2021 ◽

Author(s):

Seon-Gyeong Lee ◽

Namwoo Kim ◽

In Bae Park ◽

Jun Hong Park ◽

Kyungjae Myung

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Dna Damage Response ◽

Cellular Response ◽

Whole Body ◽

Nuclear Antigen ◽

Clinical Approach ◽

Γ Irradiation ◽

Tissue Specific ◽

Damage Response

Abstract Background Genomic instability is a hallmark of various cancers, and DNA repair is an essential process for maintaining genomic integrity. Mammalian cells have developed various DNA repair mechanisms in response to DNA damage. Compared to the cellular response to DNA damage, the in vivo DNA damage response (DDR) of specific tissues has not been studied extensively. Objective In this study, mice were exposed to whole-body gamma (γ)-irradiation to evaluate the specific DDR of various tissues. We treated male C57BL6/J mice with γ-irradiation at different doses, and the DDR protein levels in different tissues were analyzed. Results The level of gamma-H2A histone family member X (γH2AX) increased in most organs after exposure to γ-irradiation. In particular, the liver, lung, and kidney tissues showed higher γH2AX induction upon DNA damage, compared to that in the brain, muscle, and testis tissues. RAD51 was highly expressed in the testis, irrespective of irradiation. The levels of proliferating cell nuclear antigen (PCNA) and ubiquitinated PCNA increased in lung tissues upon irradiation, suggesting that the post-replication repair may mainly operate in the lungs in response to γ-irradiation. Conclusion These results suggest that each tissue has a preferable repair mechanism in response to γ-irradiation. Therefore, the understanding and application of tissue-specific DNA damage responses could improve the clinical approach of radiotherapy for treating specific cancers.

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