scholarly journals Molecular basis of chromatin remodeling by Rhp26, a yeast CSB ortholog

2019 ◽  
Vol 116 (13) ◽  
pp. 6120-6129 ◽  
Author(s):  
Wei Wang ◽  
Jun Xu ◽  
Oliver Limbo ◽  
Jia Fei ◽  
George A. Kassavetis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Molecular Mechanism ◽  
Chromatin Remodeling ◽  
Molecular Basis ◽  
Dna Damage Repair ◽  
Genome Integrity ◽  
Chromatin Remodelers ◽  
Free Dna ◽  
Damage Repair

CSB/ERCC6 belongs to an orphan subfamily of SWI2/SNF2-related chromatin remodelers and plays crucial roles in gene expression, DNA damage repair, and the maintenance of genome integrity. The molecular basis of chromatin remodeling by Cockayne syndrome B protein (CSB) is not well understood. Here we investigate the molecular mechanism of chromatin remodeling by Rhp26, aSchizosaccharomyces pombeCSB ortholog. The molecular basis of chromatin remodeling and nucleosomal epitope recognition by Rhp26 is distinct from that of canonical chromatin remodelers, such as imitation switch protein (ISWI). We reveal that the remodeling activities are bidirectionally regulated by CSB-specific motifs: the N-terminal leucine-latch motif and the C-terminal coupling motif. Rhp26 remodeling activities depend mainly on H4 tails and to a lesser extent on H3 tails, but not on H2A and H2B tails. Rhp26 promotes the disruption of histone cores and the release of free DNA. Finally, we dissected the distinct contributions of two Rhp26 C-terminal regions to chromatin remodeling and DNA damage repair.

scholarly journals A Novel Role for Cathepsin S as a Potential Biomarker in Triple Negative Breast Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Richard D. A. Wilkinson ◽  
Roberta E. Burden ◽  
Sara H. McDowell ◽  
Darragh G. McArt ◽  
Stephen McQuaid ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Dna Damage ◽  
Adjuvant Therapy ◽  
Dna Damage Repair ◽  
Cathepsin S ◽  
Damage Repair ◽  
Potential Biomarker ◽  
Repair Pathways ◽  
Improved Outcome

Cathepsin S (CTSS) has previously been implicated in a number of cancer types, where it is associated with poor clinical features and outcome. To date, patient outcome in breast cancer has not been examined with respect to this protease. Here, we carried out immunohistochemical (IHC) staining of CTSS using a breast cancer tissue microarray in patients who received adjuvant therapy. We scored CTSS expression in the epithelial and stromal compartments and evaluated the association of CTSS expression with matched clinical outcome data. We observed differences in outcome based on CTSS expression, with stromal-derived CTSS expression correlating with a poor outcome and epithelial CTSS expression associated with an improved outcome. Further subtype characterisation revealed high epithelial CTSS expression in TNBC patients with improved outcome, which remained consistent across two independent TMA cohorts. Furtherin silicogene expression analysis, using both in-house and publicly available datasets, confirmed these observations and suggested high CTSS expression may also be beneficial to outcome in ER-/HER2+ cancer. Furthermore, high CTSS expression was associated with the BL1 Lehmann subgroup, which is characterised by defects in DNA damage repair pathways and correlates with improved outcome. Finally, analysis of matching IHC analysis reveals an increased M1 (tumour destructive) polarisation in macrophage in patients exhibiting high epithelial CTSS expression. In conclusion, our observations suggest epithelial CTSS expression may be prognostic of improved outcome in TNBC. Improved outcome observed with HER2+ at the gene expression level furthermore suggests CTSS may be prognostic of improved outcome in ER- cancers as a whole. Lastly, from the context of these patients receiving adjuvant therapy and as a result of its association with BL1 subgroup CTSS may be elevated in patients with defects in DNA damage repair pathways, indicating it may be predictive of tumour sensitivity to DNA damaging agents.

scholarly journals Changes in DNA Damage Repair Gene Expression and Cell Cycle Gene Expression Do Not Explain Radioresistance in Tamoxifen-Resistant Breast Cancer

2020 ◽  
Vol 28 (1) ◽  
pp. 33-40 ◽  
Author(s):  
Annemarie E. M. Post ◽  
Johan Bussink ◽  
Fred C. G. J. Sweep ◽  
Paul N. Span
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Repair ◽  
Cross Resistance ◽  
Damage Repair ◽  
Breast Cancer Cohort ◽  
Tamoxifen Resistant ◽  
Repair Genes

Tamoxifen-induced radioresistance, reported in vitro, might pose a problem for patients who receive neoadjuvant tamoxifen treatment and subsequently receive radiotherapy after surgery. Previous studies suggested that DNA damage repair or cell cycle genes are involved, and could therefore be targeted to preclude the occurrence of cross-resistance. We aimed to characterize the observed cross-resistance by investigating gene expression of DNA damage repair genes and cell cycle genes in estrogen receptor-positive MCF-7 breast cancer cells that were cultured to tamoxifen resistance. RNA sequencing was performed, and expression of genes characteristic for several DNA damage repair pathways was investigated, as well as expression of genes involved in different phases of the cell cycle. The association of differentially expressed genes with outcome after radiotherapy was assessed in silico in a large breast cancer cohort. None of the DNA damage repair pathways showed differential gene expression in tamoxifen-resistant cells compared to wild-type cells. Two DNA damage repair genes were more than two times upregulated (NEIL1 and EME2), and three DNA damage repair genes were more than two times downregulated (PCNA, BRIP1, and BARD1). However, these were not associated with outcome after radiotherapy in the TCGA breast cancer cohort. Genes involved in G1, G1/S, G2, and G2/M phases were lower expressed in tamoxifen-resistant cells compared to wild-type cells. Individual genes that were more than two times upregulated (MAPK13) or downregulated (E2F2, CKS2, GINS2, PCNA, MCM5, and EIF5A2) were not associated with response to radiotherapy in the patient cohort investigated. We assessed the expression of DNA damage repair genes and cell cycle genes in tamoxifen-resistant breast cancer cells. Though several genes in both pathways were differentially expressed, these could not explain the cross-resistance for irradiation in these cells, since no association to response to radiotherapy in the TCGA breast cancer cohort was found.

Bortezomib Enhances Melphalan Response by Altering Fanconi Anemia (FA)/BRCA Pathway Expression and Function.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 840-840 ◽  
Author(s):  
Danielle N. Yarde ◽  
Lori A. Hazlehurst ◽  
Vasco A. Oliveira ◽  
Qing Chen ◽  
William S. Dalton
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Repair ◽  
Low Dose ◽  
Dna Damage Repair ◽  
Myeloma Cell ◽  
Myeloma Cells ◽  
Multiple Myeloma Cell ◽  
Damage Repair ◽  
Pre Treatment

Abstract The FA/BRCA pathway is involved in DNA damage repair and its importance in oncogenesis has only recently been implicated. Briefly, 8 FA/BRCA pathway family members facilitate the monoubiquitination of FANCD2. Upon monoubiquitination, FANCD2 translocates to the DNA repair foci where it interacts with other proteins to initiate DNA repair. Previously, we reported that the FA/BRCA pathway is upregulated in multiple myeloma cell lines selected for resistance to melphalan (Chen, et al, Blood 2005). Further, reducing FANCF in the melphalan resistant 8226/LR5 myeloma cell line partially reversed resistance, whereas overexpressing FANCF in the drug sensitive 8226/S myeloma line conferred resistance to melphalan. Others have reported, and we have also verified, that bortezomib enhances melphalan response in myeloma cells; however, the mechanism of enhanced melphalan activity in combination with bortezomib has not been reported. Based on our observation that the FA/BRCA pathway confers melphalan resistance, we hypothesized that bortezomib enhances melphalan response by targeting FA/BRCA DNA damage repair pathway genes. To investigate this hypothesis, we first analyzed FA/BRCA gene expression in 8226/S and 8226/LR5 cells treated with bortezomib, using a customized microfluidic card (to detect BRCA1, BRCA2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL, RAD51 and RAD51C) and q-PCR. Interestingly, we found that low dose (5nM) bortezomib decreased many FA/BRCA pathway genes as early as 2 hours, with maximal decreases seen at 24 hours. Specifically, 1.5- to 2.5-fold decreases in FANCA, FANCC, FANCD2, FANCE and RAD51C were seen 24 hours post bortezomib exposure. Moreover, pre-treatment of myeloma cells with low dose bortezomib followed by melphalan treatment revealed a greater than 2-fold reduction in FANCD2 gene expression levels. We also found that melphalan treatment alone enhanced FANCD2 protein expression and activation (monoubiquitination), whereas the combination treatment of bortezomib followed by melphalan decreased activation and overall expression of FANCD2 protein. Taken together, these results suggest that bortezomib enhances melphalan response in myeloma by targeting the FA/BRCA pathway. Further understanding of the role of the FA/BRCA pathway in determining melphalan response may allow for more customized and effective treatment of myeloma.

Radiation-Induced Upregulation of Gene Expression From Adenoviral Vectors Mediated by DNA Damage Repair and Regulation

2012 ◽  
Vol 83 (1) ◽  
pp. 376-384 ◽  
Author(s):  
Petri Nokisalmi ◽  
Maria Rajecki ◽  
Sari Pesonen ◽  
Sophie Escutenaire ◽  
Rabah Soliymani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Damage Repair ◽  
Adenoviral Vectors ◽  
Damage Repair ◽  
Radiation Induced

scholarly journals Relationships between chromatin remodeling and DNA damage repair induced by 8-methoxypsoralen and UVA in yeast Saccharomyces cerevisiae

2012 ◽  
Vol 35 (4 suppl 1) ◽  
pp. 1052-1059 ◽  
Author(s):  
Lavínia Almeida Cruz ◽  
Temenouga Nikolova Guecheva ◽  
Diego Bonato ◽  
João Antônio Pêgas Henriques
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Damage ◽  
Chromatin Remodeling ◽  
Dna Damage Repair ◽  
Yeast Saccharomyces Cerevisiae ◽  
Damage Repair

scholarly journals INO80 and γ-H2AX Interaction Links ATP-Dependent Chromatin Remodeling to DNA Damage Repair

Cell ◽  
2004 ◽  
Vol 119 (6) ◽  
pp. 767-775 ◽  
Author(s):  
Ashby J. Morrison ◽  
Jessica Highland ◽  
Nevan J. Krogan ◽  
Ayelet Arbel-Eden ◽  
Jack F. Greenblatt ◽  
...  
Keyword(s):  
Dna Damage ◽  
Chromatin Remodeling ◽  
Dna Damage Repair ◽  
Damage Repair

EPCO-04. RADIOTHERAPY IS ASSOCIATED WITH GLOBAL METHYLATION ALTERATIONS IN PATIENT DERIVED GLIOBLASTOMA CELL LINES

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi2-vi2
Author(s):  
Aram Modrek ◽  
David Byun ◽  
Ravesanker Ezhilarasan ◽  
Matija Snuderl ◽  
Erik Sulman
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Dna Damage ◽  
Radiation Treatment ◽  
Cpg Islands ◽  
Dna Damage Repair ◽  
Differential Methylation ◽  
Response To Therapy ◽  
Damage Repair ◽  
Genomic Regions

Abstract PURPOSE/OBJECTIVE(S) In glioblastoma, DNA methylation states are the most predictive marker of overall survival and response to therapy. Our understanding of how epigenetic states, such as DNA methylation, are “mis-repaired” after DNA damage repair is scant, hampering our ability to understand how treatment associated DNA methylation alterations may drive tumor resistance and growth. MATERIALS AND METHODS Three different patient derived IDH wild-type glioma stem cell (GSC) lines, in duplicates, were treated with radiation (20 Gray in 10 fractions vs. sham control) and allowed to recover prior to DNA methylation analysis with 850K methylation arrays. To analyze the methylation array data via bioinformatic methods we used RnBeads (version 2.4.0) and R (version 3.6.1) packages. We further focused our analysis to specific genomic regions, including CpG islands, promoters, gene bodies and CTCF motifs to understand how methylation alterations may differ between these and other genomic contexts following radiation. RESULTS There were widespread differential methylation (pre-treatment vs. radiation treatment) changes among the genomic regions examined. Interestingly, we found differential methylation changes at CTCF motifs, which play important DNA-methylation dependent roles in gene expression and chromatin architecture regulation. Hierarchical clustering, PCA and MDS analysis of DNA methylation status amongst CpG islands, promoters, gene bodies and CTCF domains revealed strong intra-sample differences, but not inter-sample differences (between GSC lines), suggesting radiation associated methylation alterations maybe loci and context dependent. CONCLUSION Radiation treatment is associated with wide-spread alterations of DNA methylation states in this patient derived glioblastoma model. Such alterations may drive gene expression changes or genomic architecture alterations that lead to treatment resistance, warranting further mechanistic investigation of the interplay between radiation induced DNA damage and local epigenetic state restoration following DNA damage repair.

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