The DNA repair transcriptome in severe COPD

Inadequate DNA repair is implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the mechanisms that underlie inadequate DNA repair in COPD are poorly understood. We applied an integrative genomic approach to identify DNA repair genes and pathways associated with COPD severity.We measured the transcriptomic changes of 419 genes involved in DNA repair and DNA damage tolerance that occur with severe COPD in three independent cohorts (n=1129). Differentially expressed genes were confirmed with RNA sequencing and used for patient clustering. Clinical and genome-wide transcriptomic differences were assessed following cluster identification. We complemented this analysis by performing gene set enrichment analysis, Z-score and weighted gene correlation network analysis to identify transcriptomic patterns of DNA repair pathways associated with clinical measurements of COPD severity.We found 15 genes involved in DNA repair and DNA damage tolerance to be differentially expressed in severe COPD. K-means clustering of COPD cases based on this 15-gene signature identified three patient clusters with significant differences in clinical characteristics and global transcriptomic profiles. Increasing COPD severity was associated with downregulation of the nucleotide excision repair pathway.Systematic analysis of the lung tissue transcriptome of individuals with severe COPD identified DNA repair responses associated with disease severity that may underlie COPD pathogenesis.

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DNA Topoisomerases in DNA Repair and DNA Damage Tolerance

DNA Damage and Repair ◽

10.1007/978-1-59259-455-9_23 ◽

1998 ◽

pp. 517-537 ◽

Cited By ~ 7

Author(s):

John L. Nitiss

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Damage Tolerance ◽

Dna Damage Tolerance ◽

Dna Topoisomerases

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Systematic analysis of mutational spectra associated with DNA repair deficiency in C. elegans

10.1101/2020.06.04.133306 ◽

2020 ◽

Cited By ~ 1

Author(s):

B Meier ◽

NV Volkova ◽

Y Hong ◽

S Bertolini ◽

V González-Huici ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Excision Repair ◽

Structural Variants ◽

Systematic Analysis ◽

C Elegans ◽

Mutational Spectra ◽

Base Substitutions ◽

Repair Pathways ◽

Complex Structural

AbstractGenome integrity is particularly important in germ cells to faithfully preserve genetic information across generations. As yet little is known about the contribution of various DNA repair pathways to prevent mutagenesis. Using the C. elegans model we analyse mutational spectra that arise in wild-type and 61 DNA repair and DNA damage response mutants cultivated over multiple generations. Overall, 44% of lines show >2-fold increased mutagenesis with a broad spectrum of mutational outcomes including changes in single or multiple types of base substitutions induced by defects in base excision or nucleotide excision repair, or elevated levels of 50-400 bp deletions in translesion polymerase mutants rev-3(pol ζ) and polh-1(pol η). Mutational signatures associated with defective homologous recombination fall into two classes: 1) mutants lacking brc-1/BRCA1 or rad-51/RAD51 paralogs show elevated base substitutions, indels and structural variants, while 2) deficiency for MUS-81/MUS81 and SLX-1/SLX1 nucleases, and HIM-6/BLM, HELQ-1/HELQ and RTEL-1/RTEL1 helicases primarily cause structural variants. Genome-wide investigation of mutagenesis patterns identified elevated rates of tandem duplications often associated with inverted repeats in helq-1 mutants, and a unique pattern of ‘translocation’ events involving homeologous sequences in rip-1 paralog mutants. atm-1/ATM DNA damage checkpoint mutants harboured complex structural variants enriched in subtelomeric regions, and chromosome end-to-end fusions. Finally, while inactivation of the p53-like gene cep-1 did not affect mutagenesis, combined brc-1 cep-1 deficiency displayed increased, locally clustered mutagenesis. In summary, we provide a global view of how DNA repair pathways prevent germ cell mutagenesis.

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Maturation of telomere 3’-overhangs is linked to the replication stress response

10.1101/2020.08.27.269621 ◽

2020 ◽

Author(s):

Erin E. Henninger ◽

Pascale Jolivet ◽

Emilie Fallet ◽

Mohcen Benmounah ◽

Zhou Xu ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Stress Response ◽

Ubiquitin Ligase ◽

Replication Fork ◽

Damage Tolerance ◽

Dna Helicase ◽

Dna Damage Tolerance ◽

Telomeric Repeats ◽

Telomere Replication

AbstractPassage of the replication fork through telomeric repeats necessitates additional DNA processing by DNA repair factors, to regenerate the terminal 3’-overhang structure at leading telomeres. These factors are prevented from promoting telomeric recombination or fusion by an uncharacterized mechanism. Here we show that Rad5, a DNA helicase and ubiquitin ligase involved in the DNA damage tolerance pathway, participates in this mechanism. Rad5 is enriched at telomeres during telomere replication. Accelerated senescence seen in the absence of telomerase and Rad5, can be compensated for by a pathway involving the Rad51 recombinase and counteracted by the helicase Srs2. However, this pathway is only active at short telomeres. Instead, the ubiquitous activity of Rad5 during telomere replication is necessary for the proper reconstitution of the telomeric 3’-overhang, indicating that Rad5 is required to coordinate telomere maturation during telomere replication.

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DNA Topoisomerases in DNA Repair and DNA Damage Tolerance

DNA Damage and Repair ◽

10.1385/0-89603-500-x:517 ◽

2003 ◽

pp. 517-538 ◽

Cited By ~ 1

Author(s):

John L. Nitiss

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Damage Tolerance ◽

Dna Damage Tolerance ◽

Dna Topoisomerases

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A Zebrafish Acromegaly Model Elevates DNA Damage and Impairs DNA Repair Pathways

Biology ◽

10.3390/biology7040047 ◽

2018 ◽

Vol 7 (4) ◽

pp. 47 ◽

Cited By ~ 3

Author(s):

Abdalla Elbialy ◽

Shuichi Asakawa ◽

Shugo Watabe ◽

Shigeharu Kinoshita

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Excision Repair ◽

Kidney Diseases ◽

Pathological Condition ◽

The Body ◽

Gene Set Enrichment Analysis ◽

Zebrafish Model ◽

Repair Pathways ◽

Cellular Integrity

Acromegaly is a pathological condition due to excess growth hormone (GH) secretion. Acromegaly patients exhibit a deterioration of health and many associated complications, such as cardiovascular issues, arthritis, kidney diseases, muscular weakness, and colon cancer. Since these complications are generalized throughout the body, we investigated the effect of GH excess on cellular integrity. Here, we established stable acromegaly model zebrafish lines that overexpress tilapia GH and the red fluorescence protein (RFP) reporter gene for tracking GH gene expression throughout generations, and performed RNA-Seq data analysis from different organs. Intriguingly, heatmap and Expression2Kinases (X2K) analysis revealed the enrichment of DNA damage markers in various organs. Moreover, H2A.X immunostaining analysis in acromegaly zebrafish larvae and the adult acromegaly model brain and muscle showed a robust increase in the number of DNA-damaged cells. Using Gene Set Enrichment Analysis (GSEA), we found that the acromegaly zebrafish model had impaired DNA repair pathways in the liver, such as double-strand break (DSB), homologous recombination repair (HRR), non-homologous end joining (NHEJ), nucleotide excision repair (NER), and translesion synthesis (TLS). Interestingly, the impairment of DNA repair was even more prominent in acromegaly model than in aged zebrafish (three years old). Thus, our study demonstrates that affection of cellular integrity is characteristic of acromegaly.

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