Homologous recombination 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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A conserved histone H3-H4 interface regulates DNA damage tolerance and homologous recombination during the recovery from replication stress

Molecular and Cellular Biology ◽

10.1128/mcb.00044-20 ◽

2021 ◽

Author(s):

Masafumi Hayashi ◽

Kenji Keyamura ◽

Asami Yoshida ◽

Mariko Ariyoshi ◽

Genki Akanuma ◽

...

Keyword(s):

Dna Damage ◽

Homologous Recombination ◽

Damage Tolerance ◽

Histone H3 ◽

Wild Type ◽

Dna Damage Tolerance ◽

Damage Resistance ◽

Replication Arrest ◽

Induced Mutagenesis ◽

Phase Progression

In eukaryotes, genomic DNA is packaged into nucleosomes, which are the basal components coordinating both the structures and functions of chromatin. Here we screened a collection of mutation for histone H3/H4 mutants in Saccharomyces cerevisiae that affect the DNA damage sensitivity of DNA damage tolerance (DDT)-deficient cells. We identified a class of histone H3/H4 mutations that suppress MMS sensitivity of DDT-deficient cells (hereafter we refer to as the histone SDD mutations), which likely cluster on a specific H3-H4 interface of the nucleosomes. The histone SDD mutations did not suppress the MMS sensitivity of DDT-deficient cells in the absence of Rad51, indicating that homologous recombination (HR) is responsible for DNA damage resistance. Furthermore, the histone SDD mutants showed reduced levels of PCNA ubiquitination after exposure to MMS or UV irradiation, consistent with a decreased MMS-induced mutagenesis relative to wild-type cells. We also found that histone SDD mutants lacking the INO80 chromatin remodeler impair HR-dependent recovery from MMS-induced replication arrest, resulting in defective S-phase progression and increased Rad52 foci. Taken together, our data provide novel insights into nucleosome functions, which link INO80-dependent chromatin remodeling to the regulation of DDT and HR during the recovery from replication blockage.

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Non-Recombinogenic Functions of Rad51, BRCA2, and Rad52 in DNA Damage Tolerance

Genes ◽

10.3390/genes12101550 ◽

2021 ◽

Vol 12 (10) ◽

pp. 1550

Author(s):

Félix Prado

Keyword(s):

Dna Damage ◽

Homologous Recombination ◽

Damage Tolerance ◽

Molecular Switches ◽

Strand Exchange ◽

Template Switching ◽

Replication Forks ◽

Lesion Bypass ◽

Dna Damage Tolerance ◽

Exchange Activity

The DNA damage tolerance (DDT) response is aimed to timely and safely complete DNA replication by facilitating the advance of replication forks through blocking lesions. This process is associated with an accumulation of single-strand DNA (ssDNA), both at the fork and behind the fork. Lesion bypass and ssDNA filling can be performed by translation synthesis (TLS) and template switching mechanisms. TLS uses low-fidelity polymerases to incorporate a dNTP opposite the blocking lesion, whereas template switching uses a Rad51/ssDNA nucleofilament and the sister chromatid to bypass the lesion. Rad51 is loaded at this nucleofilament by two mediator proteins, BRCA2 and Rad52, and these three factors are critical for homologous recombination (HR). Here, we review recent advances showing that Rad51, BRCA2, and Rad52 perform some of these functions through mechanisms that do not require the strand exchange activity of Rad51: the formation and protection of reversed fork structures aimed to bypass blocking lesions, and the promotion of TLS. These findings point to the central HR proteins as potential molecular switches in the choice of the mechanism of DDT.

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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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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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