scholarly journals Array CGH and gene-expression profiling reveals distinct genomic instability patterns associated with DNA repair and cell-cycle checkpoint pathways in Ewing's sarcoma

Oncogene ◽  
2007 ◽  
Vol 27 (14) ◽  
pp. 2084-2090 ◽  
Author(s):  
B I Ferreira ◽  
J Alonso ◽  
J Carrillo ◽  
F Acquadro ◽  
C Largo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Dna Repair ◽  
Gene Expression Profiling ◽  
Genomic Instability ◽  
Expression Profiling ◽  
Array Cgh ◽  
Ewing's Sarcoma ◽  
Cell Cycle Checkpoint ◽  
Cycle Checkpoint

scholarly journals Dysregulated G2 phase checkpoint recovery pathway reduces DNA repair efficiency and increases chromosomal instability in a wide range of tumours

Oncogenesis ◽  
2021 ◽  
Vol 10 (5) ◽  
Author(s):  
Madushan Fernando ◽  
Pascal H. G. Duijf ◽  
Martina Proctor ◽  
Alexander J. Stevenson ◽  
Anna Ehmann ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Genomic Instability ◽  
Chromosomal Instability ◽  
Cell Cycle Checkpoint ◽  
Phase Cell ◽  
Checkpoint Recovery ◽  
Repair Efficiency ◽  
Cycle Checkpoint ◽  
G2 Phase

AbstractDefective DNA repair is being demonstrated to be a useful target in cancer treatment. Currently, defective repair is identified by specific gene mutations, however defective repair is a common feature of cancers without these mutations. DNA damage triggers cell cycle checkpoints that are responsible for co-ordinating cell cycle arrest and DNA repair. Defects in checkpoint signalling components such as ataxia telangiectasia mutated (ATM) occur in a low proportion of cancers and are responsible for reduced DNA repair and increased genomic instability. Here we have investigated the AURKA-PLK1 cell cycle checkpoint recovery pathway that is responsible for exit from the G2 phase cell cycle checkpoint arrest. We demonstrate that dysregulation of PP6 and AURKA maintained elevated PLK1 activation to promote premature exit from only ATM, and not ATR-dependent checkpoint arrest. Surprisingly, depletion of the B55α subunit of PP2A that negatively regulates PLK1 was capable of overcoming ATM and ATR checkpoint arrests. Dysregulation of the checkpoint recovery pathway reduced S/G2 phase DNA repair efficiency and increased genomic instability. We found a strong correlation between dysregulation of the PP6-AURKA-PLK1-B55α checkpoint recovery pathway with signatures of defective homologous recombination and increased chromosomal instability in several cancer types. This work has identified an unrealised source of G2 phase DNA repair defects and chromosomal instability that are likely to be sensitive to treatments targeting defective repair.

scholarly journals Gene expression signatures but not cell cycle checkpoint functions distinguish AT carriers from normal individuals

2013 ◽  
Vol 45 (19) ◽  
pp. 907-916
Author(s):  
Liwen Zhang ◽  
Dennis A. Simpson ◽  
Cynthia L. Innes ◽  
Jeff Chou ◽  
Pierre R. Bushel ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cell Lines ◽  
Cell Cycle Checkpoint ◽  
G2 Checkpoint ◽  
P53 Signaling ◽  
Normal Individuals ◽  
Gene Expression Signatures ◽  
Cycle Checkpoint ◽  
Atm Cell

Ataxia telangiectasia (AT) is a rare autosomal recessive disease caused by mutations in the ataxia telangiectasia-mutated gene ( ATM). AT carriers with one mutant ATM allele are usually not severely affected although they carry an increased risk of developing cancer. There has not been an easy and reliable diagnostic method to identify AT carriers. Cell cycle checkpoint functions upon ionizing radiation (IR)-induced DNA damage and gene expression signatures were analyzed in the current study to test for differential responses in human lymphoblastoid cell lines with different ATM genotypes. While both dose- and time-dependent G1 and G2 checkpoint functions were highly attenuated in ATM−/− cell lines, these functions were preserved in ATM+/− cell lines equivalent to ATM+/+ cell lines. However, gene expression signatures at both baseline (consisting of 203 probes) and post-IR treatment (consisting of 126 probes) were able to distinguish ATM+/− cell lines from ATM+/+ and ATM−/− cell lines. Gene ontology (GO) and pathway analysis of the genes in the baseline signature indicate that ATM function-related categories, DNA metabolism, cell cycle, cell death control, and the p53 signaling pathway, were overrepresented. The same analyses of the genes in the IR-responsive signature revealed that biological categories including response to DNA damage stimulus, p53 signaling, and cell cycle pathways were overrepresented, which again confirmed involvement of ATM functions. The results indicate that AT carriers who have unaffected G1 and G2 checkpoint functions can be distinguished from normal individuals and AT patients by expression signatures of genes related to ATM functions.

scholarly journals DNA repair and cell cycle checkpoint defects in a mouse model of ‘BRCAness’ are partially rescued by 53BP1 deletion

Cell Cycle ◽  
2018 ◽  
Vol 17 (7) ◽  
pp. 881-891 ◽  
Author(s):  
Sarah M. Misenko ◽  
Dharm S. Patel ◽  
Joonyoung Her ◽  
Samuel F. Bunting
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Mouse Model ◽  
Cell Cycle Checkpoint ◽  
Cycle Checkpoint

Gene Expression Profiling Reveals a Crucial Role for C/EBPbeta in Proliferation Pathways of ALK+ ALCL Cell Lines

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2818-2818
Author(s):  
Irina Bonzheim ◽  
Martin Irmler ◽  
Natasa Anastasov ◽  
Margit Klier ◽  
Johannes Beckers ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Statistical Analysis ◽  
Gene Expression Profiling ◽  
Cell Lines ◽  
Expression Profiling ◽  
Leucine Zipper ◽  
Cellular Proliferation ◽  
Kinase Activity ◽  
Large Cell

Abstract Introduction: ALK+ anaplastic large cell lymphomas (ALCL) overexpress C/EBPβ, as a consequence of NPM-ALK kinase activity. C/EBPβ is a leucine zipper transcription factor, which plays a major role in cellular differentiation, inflammation, proliferation and metabolism control. To determine the role of C/EBPβ in ALK+ ALCL transformation, and to identify its downstream targets, a highly specific C/EBPβ-shRNA was used to knockdown C/EBPβ. The consequences of C/EBPβ gene-silencing were analyzed by gene expression profiling. Materials and Methods: Four ALK+ ALCL cell lines, SUDHL-1, Kijk, Karpas 299 and SUP-M2 were transfected with lentivirus containing the C/EBPβ shRNA or the vector without shRNA in triplicates. Western Blot analysis and qRT-PCR were performed to quantify the knockdown effect. At day three after infection, RNA was extracted and used for Gene Chip expression analysis (Affymetrix). Using Anova software for statistical analysis, we identified genes, which were regulated in all four cell lines. The effect of C/EBPβ knockdown on proliferation, cell cycle, and viability was analyzed by MTT assay and FACS analysis. Results: In all four ALK+ ALCL, efficient C/EBPβ knockdown resulted in profound growth retardation (up to 84%) compared to control cells after 6 days of infection, and a clear shift from the S phase to the G1 phase in the cell cycle was observed. To identify genes regulated by C/EBPβ in all four cell lines, we performed statistical analysis applying a false discovery rate of 20%, and accepted only genes with a >1,1 and <0,9 fold ratio. We identfied 435 genes regulated after C/EBPβ knockdown (117 upregulated, 318 downregulated). Classification of the differentially expressed genes into biological categories revealed overrepresentation of genes involved in the regulation of kinase activity, cell cycle and proliferation, lymphocyte differentiation, and metabolic processes. In particular, kinases involved in the regulation of JNK activity, which have been shown previously to be involved in proliferation of ALCL, were highly affected by C/EBPβ knockdown. Genomatix Bibliosphere Pathway Analysis revealed C/EBPβ to be connected to pathways involving cell cycle (RUNX3, CCNG1, CDKN2A), apoptosis (FAS, PTPRC, BCL2A1, BIRC3) and MAPK cascades (TRIB1 and several MAP3Ks). Several of the genes identified contain known C/EBPβ binding sites. Conclusions: C/EBPβ silencing induces growth arrest in ALK+ALCL, which correlates with differential expression of genes involved in cell cycle, apoptosis and differentiation. This study reveals C/EBPβ as a master transcription regulator of NPM-ALK induced cellular proliferation, and therefore, an ideal candidate for targeted therapeutic intervention.

scholarly journals Kinase-dead ATM protein causes genomic instability and early embryonic lethality in mice

2012 ◽  
Vol 198 (3) ◽  
pp. 305-313 ◽  
Author(s):  
Kenta Yamamoto ◽  
Yunyue Wang ◽  
Wenxia Jiang ◽  
Xiangyu Liu ◽  
Richard L. Dubois ◽  
...  
Keyword(s):  
Dna Repair ◽  
Embryonic Development ◽  
Genomic Instability ◽  
Cell Cycle Checkpoint ◽  
End Joining ◽  
Atm Kinase ◽  
Class Switch ◽  
Early Embryonic Lethality ◽  
Cycle Checkpoint ◽  
Atm Protein

Ataxia telangiectasia (A-T) mutated (ATM) kinase orchestrates deoxyribonucleic acid (DNA) damage responses by phosphorylating numerous substrates implicated in DNA repair and cell cycle checkpoint activation. A-T patients and mouse models that express no ATM protein undergo normal embryonic development but exhibit pleiotropic DNA repair defects. In this paper, we report that mice carrying homozygous kinase-dead mutations in Atm (AtmKD/KD) died during early embryonic development. AtmKD/− cells exhibited proliferation defects and genomic instability, especially chromatid breaks, at levels higher than Atm−/− cells. Despite this increased genomic instability, AtmKD/− lymphocytes progressed through variable, diversity, and joining recombination and immunoglobulin class switch recombination, two events requiring nonhomologous end joining, at levels comparable to Atm−/− lymphocytes. Together, these results reveal an essential function of ATM during embryogenesis and an important function of catalytically inactive ATM protein in DNA repair.

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