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 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 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 DNA Damage Tolerance Pathway Choice Through Uls1 Modulation of Srs2 SUMOylation in Saccharomyces cerevisiae

Genetics ◽  
2017 ◽  
Vol 206 (1) ◽  
pp. 513-525 ◽  
Author(s):  
Karol Kramarz ◽  
Seweryn Mucha ◽  
Ireneusz Litwin ◽  
Anna Barg-Wojas ◽  
Robert Wysocki ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Damage ◽  
Damage Tolerance ◽  
Dna Damage Tolerance ◽  
Pathway Choice

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.

DNA damage bypass pathways and their effect on mutagenesis in yeast

2020 ◽  
Author(s):  
Matan Arbel ◽  
Batia Liefshitz ◽  
Martin Kupiec
Keyword(s):  
Dna Damage ◽  
Damage Tolerance ◽  
Genetic Research ◽  
Tolerance Mechanisms ◽  
Dna Damage Tolerance ◽  
Yeast Saccharomyces Cerevisiae ◽  
Open Questions ◽  
Repair Mechanisms ◽  
Post Replication Repair ◽  
Error Prone Repair

ABSTRACT What is the origin of mutations? In contrast to the naïve notion that mutations are unfortunate accidents, genetic research in microorganisms has demonstrated that most mutations are created by genetically encoded error-prone repair mechanisms. However, error-free repair pathways also exist, and it is still unclear how cells decide when to use one repair method or the other. Here, we summarize what is known about the DNA damage tolerance mechanisms (also known as post-replication repair) for perhaps the best-studied organism, the yeast Saccharomyces cerevisiae. We describe the latest research, which has established the existence of at least two error-free and two error-prone inter-related mechanisms of damage tolerance that compete for the handling of spontaneous DNA damage. We explore what is known about the induction of mutations by DNA damage. We point to potential paradoxes and to open questions that still remain unanswered.

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