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Transcription profiling of mouse Nbs1a??B/a??B Chk2-/- and Mre11ATLD1/ATLD1 Chk2-/- animals reveals Chk2 suppresses the oncogenic potential of DNA replication-associated DNA damage

ABSTRACT: The Mre11 complex (Mre11, Rad50, and Nbs1) and Chk2 have been implicated in the DNA damage response, an inducible process required for the suppression of malignancy. The Mre11 complex is predominantly required for repair and checkpoint activation in S phase, while Chk2 governs apoptosis. We examined the relationship between the Mre11 complex and Chk2 in the DNA damage response via the establishment of Nbs1âB/âB Chk2-/- and Mre11ATLD1/ATLD1 Chk2-/- mice. Chk2 deficiency did not modify the checkpoint defects or chromosomal instability of Mre11 complex mutants; however, the double mutant mice exhibited synergistic defects in DNA damage-induced p53 regulation and apoptosis. Nbs1âB/âB Chk2-/- and Mre11ATLD1/ATLD1 Chk2-/- mice were also predisposed to tumors. In contrast, DNA-PKcs deficient mice, in which G1-specific chromosome breaks are present, did not exhibit synergy with Chk2-/- mutants. These data suggest that Chk2 suppresses the oncogenic potential of DNA damage arising during S and G2 phases of the cell cycle. Experiment Overall Design: Thymocytes from Wild type (Wt), Atm-/- and Chk2-/- mice were exposed to mock 5 Gy radiation (IR). The RNA was harvested 8 hours post treatment.

ORGANISM(S): Homo sapiens

SUBMITTER: Agnes Viale

PROVIDER: E-GEOD-11436 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Chk2 suppresses the oncogenic potential of DNA replication-associated DNA damage

Project description:The Mre11 complex (Mre11, Rad50, and Nbs1) and Chk2 have been implicated in the DNA damage response, an inducible process required for the suppression of malignancy. The Mre11 complex is predominantly required for repair and checkpoint activation in S phase, while Chk2 governs apoptosis. We examined the relationship between the Mre11 complex and Chk2 in the DNA damage response via the establishment of Nbs1∆B/∆B Chk2-/- and Mre11ATLD1/ATLD1 Chk2-/- mice. Chk2 deficiency did not modify the checkpoint defects or chromosomal instability of Mre11 complex mutants; however, the double mutant mice exhibited synergistic defects in DNA damage-induced p53 regulation and apoptosis. Nbs1∆B/∆B Chk2-/- and Mre11ATLD1/ATLD1 Chk2-/- mice were also predisposed to tumors. In contrast, DNA-PKcs deficient mice, in which G1-specific chromosome breaks are present, did not exhibit synergy with Chk2-/- mutants. These data suggest that Chk2 suppresses the oncogenic potential of DNA damage arising during S and G2 phases of the cell cycle. Keywords: Global gene expression analysis, response to radiation, Nbs1∆B/∆B Chk2-/- and Mre11ATLD1/ATLD1 Chk2-/- mutant mice

2008-05-15 | GSE11436 | GEO

CDDP treatment of U2OS cells with NCOR and SMRT knock-down

Project description:We detected an interaction between checkpoint kinase Chk2 and some members of the NCOR/SMRT co-repressor complex. In order to study the role of gene repression in the checkpoint response to DNA damage, we performed RNA profiling in NCOR or SMRT knockdown cells after treztment with cisplatin. U2OS cells were transfected with siRNAs for NCOR or SMRT, grown for 2 days in complete medium, and then treated with 100 microM cisplatin (CDDP) for 6h. Biological duplicates were used for RNa profiling

2012-02-06 | E-GEOD-34226 | biostudies-arrayexpress

CDDP treatment of U2OS cells with NCOR and SMRT knock-down

2012-02-06 | GSE34226 | GEO

Mass spectrometry analysis of in vitro PLK1 phosphorylation

Project description:Polo-like kinase 1 (PLK1) protects against genome instability by ensuring timely and accurate mitotic cell division, and its activity is tightly regulated throughout the cell cycle. Although the pathways that initially activate PLK1 in G2 are well-characterized, the factors that directly regulate PLK1 in mitosis remain poorly understood. Here, we identify that human PLK1 activity is sustained by the DNA damage response kinase Checkpoint kinase 2 (Chk2) in mitosis. Chk2 directly phosphorylates PLK1 T210, a residue on its T-loop whose phosphorylation is essential for full PLK1 kinase activity. Loss of Chk2-dependent PLK1 activity causes increased mitotic errors, including chromosome misalignment, chromosome missegregation, and cytokinetic defects. Moreover, Chk2 deficiency increases sensitivity to PLK1 inhibitors, suggesting that Chk2 status may be an informative biomarker for PLK1 inhibitor efficacy. This work demonstrates that Chk2 sustains mitotic PLK1 activity and protects genome stability through discrete functions in interphase DNA damage repair and mitotic chromosome segregation.

2024-11-01 | PXD053933 | Pride

Transcription profiling of S. cerevisiae mre11, rad50 and spo11 mutants in premeiosis and meiotic prophase

Project description:Mre11, together with Rad50 and Xrs2/NBS, plays pivotal roles in homologous recombination, repair of DNA double strand breaks (DSBs), activation of damage-induced checkpoint, and telomere maintenance. Using DNA microarray assays to analyze yeast mutants (mre11delta, rad50delta, and spo11Y135F) defective for meiotic DSB formation, we demonstrate that the absence of Mre11 in yeast causes specific effects on regulation of a class of meiotic genes for spore development. The transcriptional deficiency was not observed in other DSB mutants such as rad50delta and spo11Y135F, suggesting the transcriptional defect in mre11delta is due to neither lack of meiotic DSB formation, nor disintegrity of Mre11-Rad50-Xrs2 complex.These defects were confirmed by northern and lacZ reporter gene assays. Experiment Overall Design: Gene expression data from wild type, mre11delta, rad50delta, and spo11Y135F cells in premeiosis (meiosis 0 hr) and prophase (meiosis 4 hr). Affymetrix GeneChip YG-S98 was used. All strains used were SK1 background diploid cells.

2007-10-23 | E-GEOD-6620 | biostudies-arrayexpress

Expression data from wild type, mre11delta, rad50delta, and spo11Y135F at meiosis 0 hr and 4 hr.

2007-04-10 | GSE6620 | GEO

Transcription profiling of human normal melanocytes and melamoma cell lines reveal defective cell cycle checkpoint functions in melanoma are associated with altered patterns of gene expression

Project description:Defects in DNA damage responses may underlie genetic instability and malignant progression in melanoma. Cultures of normal human melanocytes (NHMs) and melanoma lines were analyzed to determine whether global patterns of gene expression could predict the efficacy of DNA damage cell cycle checkpoints that arrest growth and suppress genetic instability. NHMs displayed effective G1 and G2 checkpoint responses to ionizing radiation-induced DNA damage. A majority of melanoma cell lines (11/16) displayed significant quantitative defects in one or both checkpoints. Melanomas with B-RAF mutations as a class displayed a significant defect in DNA damage G2 checkpoint function. In contrast the epithelial-like subtype of melanomas with wildtype N-RAS and B-RAF alleles displayed an effective G2 checkpoint but a significant defect in G1 checkpoint function. RNA expression profiling revealed that melanoma lines with defects in the DNA damage G1 checkpoint displayed reduced expression of p53 transcriptional targets, such as CDKN1A and DDB2, and enhanced expression of proliferation-associated genes, such as CDC7 and GEMININ. A Bayesian analysis tool was more accurate than significance analysis of microarrays for predicting checkpoint function using a leave-one-out method. The results suggest that defects in DNA damage checkpoints may be recognized in melanomas through analysis of gene expression. Experiment Overall Design: Normal human melanocyte and melanoma cell lines w/wo mutations in B-raf or N-ras were treated with 1.5 Gy IR irridiartion for G1 and G2 checkpoint determination. RNA was isolated from exponentially growing cultures and applied for microarray hybridizaton with Agilent 44 K (G4112A) array.

2008-06-15 | E-GEOD-7469 | biostudies-arrayexpress

Gene expression analyses in otefin mutant Drosophila ovaries

Project description:LEM Domain proteins are key components of the nuclear lamina. Mutations in LEM-D proteins cause dystrophic diseases associated with compromised adult stem cells, yet it remains unclear how LEM-D proteins support stem cell function. Studies described here use the homologue of the LEM-D protein emerin in Drosophila, Otefin (Ote) as a model to understand LEM-D protein function in adult stem cells. Loss of Ote causes female sterility due to a complex germline stem cell (GSC) phenotype that includes both an early block in germline differentiation followed by GSC death. In vivo cell cycle analysis revealed that ote mutant GSCs display a lengthened S phase.We find that loss of the DNA Damage Response (DDR) Chk2 is able to not only rescue the lengthened S phase, but also GSC death and the block in germline differentiation. Activation of detrimental checkpoint in absence of Ote is conserved in both male and female GSCs and surprisingly occurs independent of detectable canonical DDR triggers, including transposon de-repression and DNA damage. Two defects were found to occur upstream of Chk2 activation: nuclear lamina morphological defects and altered heterochromatin organization. Together, our data identify the primary cause for a compromised adult stem cell population in the absence of a LEM-D protein.

2018-07-03 | GSE95309 | GEO

Mre11 suppresses replication stress and gene amplification proficiency

Project description:Gene amplification, copy-number increases of particular genes and surrounding genomic segments, promotes cancer progression and acquired therapy resistance. Thus, understanding genetic traits that confer gene amplification proficiency is important. The primary step for gene amplification is spontaneous DNA rearrangements initiated by DNA breaks. Here we show that mammalian cells became gene amplification-proficient when we knocked down Mre11/Rad50/Nbs1 (MRN) complex, a multifunctional complex that guards the genome from DNA breaks. Cells with reduced Mre11 experienced severe replication stress, with marked increases of single-stranded breaks followed by double-stranded breaks during DNA replication. Such breaks underlay for the increase in spontaneous gene amplification. Other traits associated with replication stress, such as impaired intra-S phase checkpoint and global transcriptional changes in DNA metabolism genes also contributed to gene amplification proficiency. Our results define Mre11 deficiency as a cause of replication stress and gene amplification proficiency and provide a candidate marker for aggressive cancer phenotypes. We sequenced four samples: 2 control, GFP-expressing samples and 2 Mre11 knockdown cells

2015-03-05 | E-GEOD-59487 | biostudies-arrayexpress

OsMre11 is required for mitosis during rice growth and development

Project description:Meiotic recombination 11 (Mre11) is a relatively conserved nuclease in various species. Mre11 plays important roles in meiosis and DNA damage repair in yeast, humans and Arabidopsis, but little research has been done on mitotic DNA replication and repair in rice. Here, it was found that Mre11 was an extensively expressed gene among the various tissues and organs of rice, and loss-of-function of Mre11 resulted in severe defects of vegetative and reproductive growth, including dwarf plants, abnormally developed male and female gametes, and completely abortive seeds. The decreased number of cells in the apical meristem and the appearance of chromosomal fragments and bridges during the mitotic cell cycle in rice mre11 mutant roots revealed an essential role of OsMre11. Further research showed that DNA replication was suppressed, and a large number of DNA strand breaks occurred during the mitotic cell cycle of rice mre11 mutants. The expression of OsMre11 was up-regulated with the treatment of hydroxyurea and methyl methanesulfonate. Moreover, OsMre11 could form a complex with OsRad50 and OsNbs1, and they might function together in non-homologous end joining and homologous recombination repair pathways. These results indicated that OsMre11 plays vital roles in DNA replication and damage repair of the mitotic cell cycle, which ensure the development and fertility of rice by maintaining genome stability.

2021-01-13 | GSE163616 | GEO

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