DNA Topoisomerases in DNA Repair and DNA Damage Tolerance

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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Hereditary disorders of DNA repair and DNA damage tolerance that predispose to neoplastic transformation

Molecular Oncology ◽

10.1017/cbo9781139046947.037 ◽

2015 ◽

pp. 434-441

Author(s):

Errol C. Friedberg ◽

Roger A. Schultz

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Damage Tolerance ◽

Neoplastic Transformation ◽

Dna Damage Tolerance ◽

Hereditary Disorders

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The DNA repair transcriptome in severe COPD

European Respiratory Journal ◽

10.1183/13993003.01994-2017 ◽

2018 ◽

Vol 52 (4) ◽

pp. 1701994 ◽

Cited By ~ 7

Author(s):

Maor Sauler ◽

Maxime Lamontagne ◽

Eric Finnemore ◽

Jose D. Herazo-Maya ◽

John Tedrow ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Damage Tolerance ◽

Excision Repair ◽

Gene Set Enrichment Analysis ◽

Differentially Expressed ◽

Chronic Obstructive ◽

Dna Damage Tolerance ◽

Systematic Analysis ◽

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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