scholarly journals Mus308 Processes Oxygen and Nitrogen Ethylation DNA Damage in Germ Cells of Drosophila

2010 ◽  
Vol 2010 ◽  
pp. 1-7 ◽  
Author(s):  
Nancy Díaz-Valdés ◽  
Miguel A. Comendador ◽  
L. María Sierra
Keyword(s):  
Dna Damage ◽  
Germ Cells ◽  
Mutation Frequency ◽  
Damage Tolerance ◽  
Tolerance Mechanism ◽  
Dna Damage Tolerance ◽  
Cross Links ◽  
Higher Eukaryotes ◽  
Mutation Spectra

TheD. melanogaster mus308gene, highly conserved among higher eukaryotes, is implicated in the repair of cross-links and of O-ethylpyrimidine DNA damage, working in a DNA damage tolerance mechanism. However, despite its relevance, its possible role on the processing of different DNA ethylation damages is not clear. To obtain data on mutation frequency and on mutation spectra inmus308deficient (mus308-) conditions, the ethylating agent diethyl sulfate (DES) was analysed in postmeiotic male germ cells. These data were compared with those corresponding tomus308efficient conditions. Our results indicate that Mus308 is necessary for the processing of oxygen and N-ethylation damage, for the survival of fertilized eggs depending on the level of induced DNA damage, and for an influence of the DNA damage neighbouring sequence. These results support the role ofmus308in a tolerance mechanism linked to a translesion synthesis pathway and also to the alternative end-joinig system.

scholarly journals Participation of the HIM1 gene of yeast Saccharomyces cerevisiae in the error-free branch of post-replicative repair and role Polη in him1-dependent mutagenesis

2020 ◽  
Author(s):  
E. A. Alekseeva ◽  
T. A. Evstyukhina ◽  
V. T. Peshekhonov ◽  
V. G. Korolev
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Damage ◽  
Damage Tolerance ◽  
Dna Damage Tolerance ◽  
Uv Mutagenesis ◽  
Gene Encoding ◽  
Yeast Saccharomyces Cerevisiae ◽  
Recombination Repair ◽  
Repair Pathways

Abstract In eukaryotes, DNA damage tolerance (DDT) is determined by two repair pathways, homologous repair recombination (HRR) and a pathway controlled by the RAD6-epistatic group of genes. Monoubiquitylation of PCNA mediates an error-prone pathway, whereas polyubiquitylation stimulates an error-free pathway. The error-free pathway involves components of recombination repair; however, the factors that act in this pathway remain largely unknown. Here, we report that the HIM1 gene participates in error-free DDT. Notably, inactivation RAD30 gene encoding Polη completely suppresses him1-dependent UV mutagenesis. Furthermore, data obtained show a significant role of Polη in him1-dependent mutagenesis, especially at non-bipyrimidine sites (NBP sites). We demonstrate that him1 mutation significantly reduces the efficiency of the induction expression of RNR genes after UV irradiation. Besides, this paper presents evidence that significant increase in the dNTP levels suppress him1-dependent mutagenesis. Our findings show that Polη responsible for him1-dependent mutagenesis.

scholarly journals DNA damage tolerance in hematopoietic stem and progenitor cells in mice

2017 ◽  
Vol 114 (33) ◽  
pp. E6875-E6883 ◽  
Author(s):  
Bas Pilzecker ◽  
Olimpia Alessandra Buoninfante ◽  
Paul van den Berk ◽  
Cesare Lancini ◽  
Ji-Ying Song ◽  
...  
Keyword(s):  
Dna Damage ◽  
Progenitor Cells ◽  
Damage Tolerance ◽  
Premature Aging ◽  
Intrinsic Defect ◽  
Dna Damage Tolerance ◽  
Erythroid Progenitor ◽  
Hematopoietic Stem ◽  
Fork Stalling

DNA damage tolerance (DDT) enables bypassing of DNA lesions during replication, thereby preventing fork stalling, replication stress, and secondary DNA damage related to fork stalling. Three modes of DDT have been documented: translesion synthesis (TLS), template switching (TS), and repriming. TLS and TS depend on site-specific PCNA K164 monoubiquitination and polyubiquitination, respectively. To investigate the role of DDT in maintaining hematopoietic stem cells (HSCs) and progenitors, we used PcnaK164R/K164R mice as a unique DDT-defective mouse model. Analysis of the composition of HSCs and HSC-derived multipotent progenitors (MPPs) revealed a significantly reduced number of HSCs, likely owing to increased differentiation of HSCs toward myeloid/erythroid-associated MPP2s. This skewing came at the expense of the number of lymphoid-primed MPP4s, which appeared to be compensated for by increased MPP4 proliferation. Furthermore, defective DDT decreased the numbers of MPP-derived common lymphoid progenitor (CLP), common myeloid progenitor (CMP), megakaryocyte-erythroid progenitor (MEP), and granulocyte-macrophage progenitor (GMP) cells, accompanied by increased cell cycle arrest in CMPs. The HSC and MPP phenotypes are reminiscent of premature aging and stressed hematopoiesis, and indeed progressed with age and were exacerbated on cisplatin exposure. Bone marrow transplantations revealed a strong cell intrinsic defect of DDT-deficient HSCs in reconstituting lethally irradiated mice and a strong competitive disadvantage when cotransplanted with wild-type HSCs. These findings indicate a critical role of DDT in maintaining HSCs and progenitor cells, and in preventing premature aging.

Role of yeast Rad5 and its human orthologs, HLTF and SHPRH in DNA damage tolerance

DNA Repair ◽  
2010 ◽  
Vol 9 (3) ◽  
pp. 257-267 ◽  
Author(s):  
Ildiko Unk ◽  
Ildikó Hajdú ◽  
András Blastyák ◽  
Lajos Haracska
Keyword(s):  
Dna Damage ◽  
Damage Tolerance ◽  
Dna Damage Tolerance ◽  
Human Orthologs

scholarly journals Eukaryotic Translesion Polymerases and Their Roles and Regulation in DNA Damage Tolerance

2009 ◽  
Vol 73 (1) ◽  
pp. 134-154 ◽  
Author(s):  
Lauren S. Waters ◽  
Brenda K. Minesinger ◽  
Mary Ellen Wiltrout ◽  
Sanjay D'Souza ◽  
Rachel V. Woodruff ◽  
...  
Keyword(s):  
Dna Damage ◽  
Damage Tolerance ◽  
Dna Lesions ◽  
Dna Damage Tolerance ◽  
Current State ◽  
Eukaryotic Dna ◽  
A Cell ◽  
Translesion Polymerases ◽  
Stalled Replication Forks

SUMMARY DNA repair and DNA damage tolerance machineries are crucial to overcome the vast array of DNA damage that a cell encounters during its lifetime. In this review, we summarize the current state of knowledge about the eukaryotic DNA damage tolerance pathway translesion synthesis (TLS), a process in which specialized DNA polymerases replicate across from DNA lesions. TLS aids in resistance to DNA damage, presumably by restarting stalled replication forks or filling in gaps that remain in the genome due to the presence of DNA lesions. One consequence of this process is the potential risk of introducing mutations. Given the role of these translesion polymerases in mutagenesis, we discuss the significant regulatory mechanisms that control the five known eukaryotic translesion polymerases: Rev1, Pol ζ, Pol κ, Pol η, and Pol ι.

Chemical Protein Polyubiquitination Reveals the Role of a Noncanonical Polyubiquitin Chain in DNA Damage Tolerance

2014 ◽  
Vol 9 (8) ◽  
pp. 1685-1691 ◽  
Author(s):  
Kun Yang ◽  
Ping Gong ◽  
Parikshit Gokhale ◽  
Zhihao Zhuang
Keyword(s):  
Dna Damage ◽  
Damage Tolerance ◽  
Polyubiquitin Chain ◽  
Dna Damage Tolerance

scholarly journals Noncanonical Role of the 9-1-1 Clamp in the Error-Free DNA Damage Tolerance Pathway

2013 ◽  
Vol 49 (3) ◽  
pp. 536-546 ◽  
Author(s):  
Georgios Ioannis Karras ◽  
Marco Fumasoni ◽  
Grzegorz Sienski ◽  
Fabio Vanoli ◽  
Dana Branzei ◽  
...  
Keyword(s):  
Dna Damage ◽  
Damage Tolerance ◽  
Dna Damage Tolerance ◽  
Free Dna

scholarly journals The Chromatin-binding Protein Spn1 contributes to Genome Instability in Saccharomyces cerevisiae

2018 ◽  
Author(s):  
Alison K. Thurston ◽  
Catherine A. Radebaugh ◽  
Adam R. Almeida ◽  
Juan Lucas Argueso ◽  
Laurie A. Stargell
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Cycle ◽  
Dna Damage ◽  
Genome Stability ◽  
Damage Tolerance ◽  
Genome Instability ◽  
Chromatin Binding ◽  
Dna Damage Tolerance ◽  
Template Switch

AbstractCells expend a large amount of energy to maintain their DNA sequence. DNA repair pathways, cell cycle checkpoint activation, proofreading polymerases, and chromatin structure are ways in which the cell minimizes changes to the genome. During replication, the DNA damage tolerance pathway allows the replication forks to bypass damage on the template strand. This avoids prolonged replication fork stalling, which can contribute to genome instability. The DNA damage tolerance pathway includes two sub-pathways: translesion synthesis and template switch. Post-translational modification of PCNA and the histone tails, cell cycle phase, and local DNA structure have all been shown to influence sub-pathway choice. Chromatin architecture contributes to maintaining genome stability by providing physical protection of the DNA and by regulating DNA processing pathways. As such, chromatin-binding factors have been implicated in maintaining genome stability. Using Saccharomyces cerevisiae, we examined the role of Spn1, a chromatin binding and transcription elongation factor, in DNA damage tolerance. Expression of a mutant allele of SPN1 results in increased resistance to the DNA damaging agent methyl methanesulfonate, lower spontaneous and damage-induced mutation rates, along with increased chronological lifespan. We attribute these effects to an increased usage of the template switch branch of the DNA damage tolerance pathway in the spn1 strain. This provides evidence for a role of wild type Spn1 in promoting genome instability, as well as having ties to overcoming replication stress and contributing to chronological aging.

scholarly journals The Human RAD5 Homologs, HLTF and SHPRH, Have Separate Functions in DNA Damage Tolerance Dependent on the DNA Lesion Type

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 463
Author(s):  
Mareike Seelinger ◽  
Caroline Krogh Søgaard ◽  
Marit Otterlei
Keyword(s):  
Dna Damage ◽  
Cell Line ◽  
Cell Lines ◽  
Mutation Frequency ◽  
Damage Tolerance ◽  
Ring Finger ◽  
Vital Role ◽  
Dna Lesions ◽  
Double Knockout ◽  
Dna Damage Tolerance

Helicase-like transcription factor (HLTF) and SNF2, histone-linker, PHD and RING finger domain-containing helicase (SHPRH), the two human homologs of yeast Rad5, are believed to have a vital role in DNA damage tolerance (DDT). Here we show that HLTF, SHPRH and HLTF/SHPRH knockout cell lines show different sensitivities towards UV-irradiation, methyl methanesulfonate (MMS), cisplatin and mitomycin C (MMC), which are drugs that induce different types of DNA lesions. In general, the HLTF/SHPRH double knockout cell line was less sensitive than the single knockouts in response to all drugs, and interestingly, especially to MMS and cisplatin. Using the SupF assay, we detected an increase in the mutation frequency in HLTF knockout cells both after UV- and MMS-induced DNA lesions, while we detected a decrease in mutation frequency over UV lesions in the HLTF/SHPRH double knockout cells. No change in the mutation frequency was detected in the HLTF/SHPRH double knockout cell line after MMS treatment, even though these cells were more resistant to MMS and grew faster than the other cell lines after treatment with DNA damaging agents. This phenotype could possibly be explained by a reduced activation of checkpoint kinase 2 (CHK2) and MCM2 (a component of the pre-replication complex) after MMS treatment in cells lacking SHPRH. Our data reveal both distinct and common roles of the human RAD5 homologs dependent on the nature of DNA lesions, and identified SHPRH as a regulator of CHK2, a central player in DNA damage response.

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