scholarly journals Lifespan prolonging mechanisms and insulin upregulation without fat accumulation in long-lived reproductives of a higher termite

2022 ◽  
Vol 5 (1) ◽  
Author(s):  
Sarah Séité ◽  
Mark C. Harrison ◽  
David Sillam-Dussès ◽  
Roland Lupoli ◽  
Tom J. M. Van Dooren ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Molecular Mechanisms ◽  
Dna Damage Repair ◽  
Fat Storage ◽  
Fat Accumulation ◽  
Damage Repair ◽  
Mitochondrial Functions ◽  
Anti Oxidant ◽  
Fat Bodies

AbstractKings and queens of eusocial termites can live for decades, while queens sustain a nearly maximal fertility. To investigate the molecular mechanisms underlying their long lifespan, we carried out transcriptomics, lipidomics and metabolomics in Macrotermes natalensis on sterile short-lived workers, long-lived kings and five stages spanning twenty years of adult queen maturation. Reproductives share gene expression differences from workers in agreement with a reduction of several aging-related processes, involving upregulation of DNA damage repair and mitochondrial functions. Anti-oxidant gene expression is downregulated, while peroxidability of membranes in queens decreases. Against expectations, we observed an upregulated gene expression in fat bodies of reproductives of several components of the IIS pathway, including an insulin-like peptide, Ilp9. This pattern does not lead to deleterious fat storage in physogastric queens, while simple sugars dominate in their hemolymph and large amounts of resources are allocated towards oogenesis. Our findings support the notion that all processes causing aging need to be addressed simultaneously in order to prevent it.

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.

scholarly journals Recruitment of the Type B Histone Acetyltransferase Hat1p to Chromatin Is Linked to DNA Double-Strand Breaks

2006 ◽  
Vol 26 (9) ◽  
pp. 3649-3658 ◽  
Author(s):  
Song Qin ◽  
Mark R. Parthun
Keyword(s):  
Dna Damage ◽  
Molecular Mechanisms ◽  
Dna Damage Repair ◽  
Strand Break ◽  
Double Strand Break ◽  
Similar Distribution ◽  
Tail Domain ◽  
Type B ◽  
Direct Role ◽  
Damage Repair

ABSTRACT Type B histone acetyltransferases are thought to catalyze the acetylation of the NH2-terminal tails of newly synthesized histones. Although Hat1p has been implicated in cellular processes, such as telomeric silencing and DNA damage repair, the underlying molecular mechanisms by which it functions remain elusive. In an effort to understand how Hat1p is involved in the process of DNA double-strand break (DSB) repair, we examined whether Hat1p is directly recruited to sites of DNA damage. Following induction of the endonuclease HO, which generates a single DNA DSB at the MAT locus, we found that Hat1p becomes associated with chromatin near the site of DNA damage. The nuclear Hat1p-associated histone chaperone Hif1p is also recruited to an HO-induced DSB with a similar distribution. In addition, while the acetylation of all four histone H4 NH2-terminal tail domain lysine residues is increased following DSB formation, only the acetylation of H4 lysine 12, the primary target of Hat1p activity, is dependent on the presence of Hat1p. Kinetic analysis of Hat1p localization indicates that it is recruited after the phosphorylation of histone H2A S129 and concomitant with the recombinational-repair factor Rad52p. Surprisingly, Hat1p is still recruited to chromatin in strains that cannot repair an HO-induced double-strand break. These results indicate that Hat1p plays a direct role in DNA damage repair and is responsible for specific changes in histone modification that occur during the course of recombinational DNA repair.

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 Deletions of 5q Promote Genome Instability in TP53-Mutant MDS/AML

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1244-1244
Author(s):  
Andreea Reilly ◽  
Stephanie Busch ◽  
Janis L. Abkowitz ◽  
Pamela S. Becker ◽  
Sergei Doulatov
Keyword(s):  
Dna Damage ◽  
Chromosomal Instability ◽  
Molecular Mechanisms ◽  
Genome Instability ◽  
Dna Damage Repair ◽  
Normal Karyotype ◽  
Complex Karyotype ◽  
Differentiation Potential ◽  
Tp53 Mutations ◽  
Damage Repair

Purpose TP53 mutations in myeloid neoplasms (MDS/AML) are associated with high-risk disease, poor outcome, and complex karyotype. The molecular mechanisms which lead to global chromosomal instability remain poorly understood. Loss of 5q [del(5q)] is the most frequent cytogenetic abnormality associated with TP53 mutations suggesting that haploinsufficiency of genes on 5q contributes to chromosomal instability. Methods We reprogrammed MDS/AML patient samples to establish genetically accurate iPSC lines from preleukemic subclones. We generated iPSCs with TP53 mutations and del(5q), differentiated them to hematopoietic progenitors (HPCs), and determined the contribution of del(5q) to genome instability. Results By reprogramming MDS/AML complex karyotype patient samples, we identified iPSCs with heterozygous TP53 mutations (TP53-only), as well as iPSCs with TP53 mutations and del5(q22-q31) (TP53;del5q), and an otherwise normal karyotype. HPCs derived from TP53;del5q iPSCs had decreased multilineage differentiation potential compared to the TP53-only HPCs. Gene expression analysis of TP53;del5q HPCs revealed downregulation of genes involved in chromosome segregation and DNA damage repair. Following irradiation TP53;del5q cells had significantly delayed DNA damage repair kinetics. In order to evaluate the effects of TP53 and del(5q) on chromosomal segregation during stress, we arrested the cells in mitosis by disrupting the mitotic spindle and quantified the induction of micronuclei, a marker of chromosomal instability that occurs due to lagging chromosomes. TP53;del5q cells had an increased frequency of micronuclei formation compared to TP53-only cells. We also detected micronuclei in primary AML patient samples. Micronuclei in iPSC-HPCs and primary patient cells had disrupted nuclear envelope and DNA damage marked by y-H2AX. Conclusions Our reprogramming approach revealed that TP53 mutations are disease-initiating and frequently followed by 5q loss. We propose that del(5q) cooperates with mutant TP53 to promote genome instability via two distinct mechanisms: classical double-stranded break repair and micronuclei formation. The latter is associated with global chromosomal instability, aneuploidy, and chromothripsis. We propose that loss of 5q accelerates genome instability in TP53-mutant cells which over time impedes normal hematopoietic differentiation and leads to complex karyotype. Disclosures Becker: The France Foundation: Honoraria; Accordant Health Services/Caremark: Consultancy; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding.

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.

scholarly journals Interactome Analysis Reveals a Novel Role for RAD6 in the Regulation of Proteasome Activity and Localization in Response to DNA Damage

2016 ◽  
Vol 37 (6) ◽  
Author(s):  
Hongli An ◽  
Lu Yang ◽  
Chen Wang ◽  
Zhixue Gan ◽  
Haihui Gu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Dna Damage Repair ◽  
Repair Process ◽  
Proteasome Activity ◽  
Nuclear Antigen ◽  
Ppi Networks ◽  
Damage Repair ◽  
Repair Pathways

ABSTRACT RAD6, an E2 ubiquitin-conjugating enzyme, is a key node for determining different DNA damage repair pathways, controlling both the error-prone and the error-free DNA damage repair pathways through differential regulation of the ubiquitination of the proliferating cell nuclear antigen (PCNA) protein. However, whether other pathways are involved in the RAD6-mediated regulation of DNA damage repair is still unclear. To deeply understand the molecular mechanisms of RAD6 in DNA damage repair, we performed a proteomic analysis and identified the changes of the protein-protein interaction (PPI) networks of RAD6 before and after X-ray irradiation. Furthermore, our study indicated that a proteasome-related event is likely involved in the DNA damage repair process. Moreover, we found that RAD6 promotes proteasome activity and nuclear translocation by enhancing the degradation of PSMF1 and the lamin B receptor (LBR). Therefore, we provide a novel pathway that is employed by RAD6 in response to DNA damage.

Altered REDD1, myostatin, and Akt/mTOR/FoxO/MAPK signaling in streptozotocin-induced diabetic muscle atrophy

2012 ◽  
Vol 302 (3) ◽  
pp. E307-E315 ◽  
Author(s):  
Juha J. Hulmi ◽  
Mika Silvennoinen ◽  
Maarit Lehti ◽  
Riikka Kivelä ◽  
Heikki Kainulainen
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Signaling Pathways ◽  
Muscle Atrophy ◽  
Dna Damage Repair ◽  
Mapk Signaling ◽  
Atp Production ◽  
Translational Repressor ◽  
Protein Ubiquitination ◽  
Damage Repair

Type 1 diabetes, if poorly controlled, leads to skeletal muscle atrophy, decreasing the quality of life. We aimed to search highly responsive genes in diabetic muscle atrophy in a common diabetes model and to further characterize associated signaling pathways. Mice were killed 1, 3, or 5 wk after streptozotocin or control. Gene expression of calf muscles was analyzed using microarray and protein signaling with Western blotting. We identified translational repressor protein REDD1 (regulated in development and DNA damage responses) that increased seven- to eightfold and was associated with muscle atrophy in diabetes. The diabetes-induced increase in REDD1 was confirmed at the protein level. This result was accompanied by the increased gene expression of DNA damage/repair pathways and decreased expression in ATP production pathways. Concomitantly, increased phosphorylation of AMPK and dephosphorylation of the Akt/mTOR/S6K1/FoxO pathway of proteins were observed together with increased protein ubiquitination. These changes were especially evident during the first 3 wk, along with the strong decrease in muscle mass. Diabetes also induced an increase in myostatin protein and decreased MAPK signaling. These, together with decreased serum insulin and increased serum glucose, remained altered throughout the 5-wk period. In conclusion, diabetic myopathy induced by streptozotocin led to alteration of multiple signaling pathways. Of those, increased REDD1 and myostatin together with decreased Akt/mTOR/FoxO signaling are associated with diabetic muscle atrophy. The increased REDD1 and decreased Akt/mTOR/FoxO signaling followed a similar time course and thus may be explained, in part, by increased expression of genes in DNA damage/repair and possibly also decrease in ATP-production pathways.

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