scholarly journals Piecing Together How Peroxiredoxins Maintain Genomic Stability

Antioxidants ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 177 ◽  
Author(s):  
James West ◽  
Trevor Roston ◽  
Joseph David ◽  
Kristin Allan ◽  
Matthew Loberg
Keyword(s):  
Genome Stability ◽  
Genomic Stability ◽  
Tumor Formation ◽  
Cancer Etiology ◽  
Yeast Saccharomyces Cerevisiae ◽  
Thioredoxin System ◽  
Potential Link ◽  
Thiol Oxidoreductases ◽  
Redox Switch ◽  
Defense Protein

Peroxiredoxins, a highly conserved family of thiol oxidoreductases, play a key role in oxidant detoxification by partnering with the thioredoxin system to protect against oxidative stress. In addition to their peroxidase activity, certain types of peroxiredoxins possess other biochemical activities, including assistance in preventing protein aggregation upon exposure to high levels of oxidants (molecular chaperone activity), and the transduction of redox signals to downstream proteins (redox switch activity). Mice lacking the peroxiredoxin Prdx1 exhibit an increased incidence of tumor formation, whereas baker’s yeast (Saccharomyces cerevisiae) lacking the orthologous peroxiredoxin Tsa1 exhibit a mutator phenotype. Collectively, these findings suggest a potential link between peroxiredoxins, control of genomic stability, and cancer etiology. Here, we examine the potential mechanisms through which Tsa1 lowers mutation rates, taking into account its diverse biochemical roles in oxidant defense, protein homeostasis, and redox signaling as well as its interplay with thioredoxin and thioredoxin substrates, including ribonucleotide reductase. More work is needed to clarify the nuanced mechanism(s) through which this highly conserved peroxidase influences genome stability, and to determine if this mechanism is similar across a range of species.

scholarly journals The Amazing Acrobat: Yeast’s Histone H3K56 Juggles Several Important Roles While Maintaining Perfect Balance

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 342
Author(s):  
Lihi Gershon ◽  
Martin Kupiec
Keyword(s):  
Dna Replication ◽  
Genome Stability ◽  
Entry And Exit ◽  
Yeast Saccharomyces Cerevisiae ◽  
Cellular Processes ◽  
M Phase ◽  
Dna Replication And Repair ◽  
H3k56 Acetylation ◽  
Timely Fashion ◽  
The Many

Acetylation on lysine 56 of histone H3 of the yeast Saccharomyces cerevisiae has been implicated in many cellular processes that affect genome stability. Despite being the object of much research, the complete scope of the roles played by K56 acetylation is not fully understood even today. The acetylation is put in place at the S-phase of the cell cycle, in order to flag newly synthesized histones that are incorporated during DNA replication. The signal is removed by two redundant deacetylases, Hst3 and Hst4, at the entry to G2/M phase. Its crucial location, at the entry and exit points of the DNA into and out of the nucleosome, makes this a central modification, and dictates that if acetylation and deacetylation are not well concerted and executed in a timely fashion, severe genomic instability arises. In this review, we explore the wealth of information available on the many roles played by H3K56 acetylation and the deacetylases Hst3 and Hst4 in DNA replication and repair.

scholarly journals The telomeric Cdc13–Stn1–Ten1 complex regulates RNA polymerase II transcription

2019 ◽  
Vol 47 (12) ◽  
pp. 6250-6268 ◽  
Author(s):  
Olga Calvo ◽  
Nathalie Grandin ◽  
Antonio Jordán-Pla ◽  
Esperanza Miñambres ◽  
Noelia González-Polo ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Genome Stability ◽  
Elongation Factor ◽  
Yeast Saccharomyces Cerevisiae ◽  
Replication Fork Progression ◽  
Genome Wide ◽  
Length Regulation ◽  
Transcription Regulators ◽  
Rna Polymerase Ii Transcription

Abstract Specialized telomeric proteins have an essential role in maintaining genome stability through chromosome end protection and telomere length regulation. In the yeast Saccharomyces cerevisiae, the evolutionary conserved CST complex, composed of the Cdc13, Stn1 and Ten1 proteins, largely contributes to these functions. Here, we report genetic interactions between TEN1 and several genes coding for transcription regulators. Molecular assays confirmed this novel function of Ten1 and further established that it regulates the occupancies of RNA polymerase II and the Spt5 elongation factor within transcribed genes. Since Ten1, but also Cdc13 and Stn1, were found to physically associate with Spt5, we propose that Spt5 represents the target of CST in transcription regulation. Moreover, CST physically associates with Hmo1, previously shown to mediate the architecture of S-phase transcribed genes. The fact that, genome-wide, the promoters of genes down-regulated in the ten1-31 mutant are prefentially bound by Hmo1, leads us to propose a potential role for CST in synchronizing transcription with replication fork progression following head-on collisions.

scholarly journals The RAD51 recombinase protects mitotic chromatin in human cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Isabel E. Wassing ◽  
Emily Graham ◽  
Xanita Saayman ◽  
Lucia Rampazzo ◽  
Christine Ralf ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Genome Stability ◽  
Spindle Assembly Checkpoint ◽  
De Novo ◽  
Genomic Stability ◽  
Human Cells ◽  
Genome Integrity ◽  
Chromosomal Replication ◽  
Anaphase Onset ◽  
Mitotic Chromatin

AbstractThe RAD51 recombinase plays critical roles in safeguarding genome integrity, which is fundamentally important for all living cells. While interphase functions of RAD51 in maintaining genome stability are well-characterised, its role in mitosis remains contentious. In this study, we show that RAD51 protects under-replicated DNA in mitotic human cells and, in this way, promotes mitotic DNA synthesis (MiDAS) and successful chromosome segregation. In cells experiencing mild replication stress, MiDAS was detected irrespective of mitotically generated DNA damage. MiDAS broadly required de novo RAD51 recruitment to single-stranded DNA, which was supported by the phosphorylation of RAD51 by the key mitotic regulator Polo-like kinase 1. Importantly, acute inhibition of MiDAS delayed anaphase onset and induced centromere fragility, suggesting a mechanism that prevents the satisfaction of the spindle assembly checkpoint while chromosomal replication remains incomplete. This study hence identifies an unexpected function of RAD51 in promoting genomic stability in mitosis.

scholarly journals Replication slippage between distant short repeats in Saccharomyces cerevisiae depends on the direction of replication and the RAD50 and RAD52 genes.

1995 ◽  
Vol 15 (10) ◽  
pp. 5607-5617 ◽  
Author(s):  
H T Tran ◽  
N P Degtyareva ◽  
N N Koloteva ◽  
A Sugino ◽  
H Masumoto ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Genome Stability ◽  
Genome Instability ◽  
Temperature Sensitive ◽  
Direct Repeats ◽  
Dna Polymerase Delta ◽  
Dna Double Strand Breaks ◽  
Yeast Saccharomyces Cerevisiae ◽  
Replication Slippage ◽  
Random Sequences

Small direct repeats, which are frequent in all genomes, are a potential source of genome instability. To study the occurrence and genetic control of repeat-associated deletions, we developed a system in the yeast Saccharomyces cerevisiae that was based on small direct repeats separated by either random sequences or inverted repeats. Deletions were examined in the LYS2 gene, using a set of 31- to 156-bp inserts that included inserts with no apparent potential for secondary structure as well as two quasipalindromes. All inserts were flanked by 6- to 9-bp direct repeats of LYS2 sequence, providing an opportunity for Lys+ reversion via precise excision. Reversions could arise by extended deletions involving either direct repeats or random sequences and by -1-or +2-bp frameshift mutations. The deletion breakpoints were always associated with short (3- to 9-bp) perfect or imperfect direct repeats. Compared with the POL+ strain, deletions between small direct repeats were increased as much as 100-fold, and the spectrum was changed in a temperature-sensitive DNA polymerase delta pol3-t mutant, suggesting a role for replication. The type of deletion depended on orientation relative to the origin of replication. On the basis of these results, we propose (i) that extended deletions between small repeats arise by replication slippage and (ii) that the deletions occur primarily in either the leading or lagging strand. The RAD50 and RAD52 genes, which are required for the recombinational repair of many kinds of DNA double-strand breaks, appeared to be required also for the production of up to 90% of the deletions arising between separated repeats in the pol3-t mutant, suggesting a newly identified role for these genes in genome stability and possibly replication.

scholarly journals ATRIP protects progenitor cells against DNA damage in vivo

2020 ◽  
Author(s):  
Gabriel E. Matos-Rodrigues ◽  
Paulius Grigaravicius ◽  
Bernard S. Lopez ◽  
Thomas Hofmann ◽  
Pierre-Olivier Frappart ◽  
...  
Keyword(s):  
Dna Damage ◽  
Progenitor Cells ◽  
Genome Stability ◽  
Genomic Stability ◽  
Interacting Protein ◽  
Replicative Stress ◽  
Dependent Cell ◽  
Short Life Expectancy

AbstractThe maintenance of genomic stability during the cell cycle of progenitor cells is essential for the faithful transmission of genetic information. Mutations in genes that ensure genome stability lead to human developmental syndromes. Mutations in Ataxia Telangiectasia and Rad3-related (ATR) or in ATR-interacting protein (ATRIP) lead to Seckel syndrome, which is characterized by developmental malformations and short life expectancy. While the roles of ATR in replicative stress response and chromosomal segregation are well established, it is unknown how ATRIP contributes to maintaining genomic stability in progenitor cells in vivo. Here, we generated the first mouse model to investigate ATRIP function. Conditional inactivation of Atrip in progenitor cells of the CNS and eye led to microcephaly, microphthalmia and postnatal lethality. To understand the mechanisms underlying these malformations, we used lens progenitor cells as a model and found that ATRIP loss promotes replicative stress and TP53-dependent cell death. Trp53 inactivation in Atrip-deficient progenitor cells rescued apoptosis but increased mitotic DNA damage and mitotic defects. Our findings demonstrate an essential role of ATRIP in preventing DNA damage accumulation during unchallenged replication.

scholarly journals An infection-activated redox switch promotes tumor growth

2021 ◽  
Author(s):  
Yekaterina Kovalyova ◽  
Daniel W. Bak ◽  
Elizabeth M. Gordon ◽  
Connie Fung ◽  
Jennifer H. B. Shuman ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Xenograft Model ◽  
Tumor Formation ◽  
Host Protein ◽  
Oxygen Species ◽  
Chemical Proteomics ◽  
Post Translational Modifications ◽  
Redox Switch ◽  
Infected Cells ◽  
H Pylori

Oxidative stress is a defining feature of most cancers, including those that stem from carcinogenic infections. Reactive oxygen species (ROS) can drive tumor formation, yet the molecular oxidation events that contribute to tumorigenesis are largely unknown. Here we show that inactivation of a single, redox-sensitive cysteine in the host protease legumain, which is oxidized during infection with the gastric cancer-causing bacterium Helicobacter pylori, accelerates tumor growth. By using chemical proteomics to map cysteine reactivity in human gastric cells, we determined that H. pylori infection induces oxidation of legumain at Cys219. Legumain oxidation, which is enhanced by the ROS-promoting bacterial oncoprotein CagA, dysregulates intracellular legumain processing and localization and decreases legumain activity in H. pylori-infected cells. We further show that the site-specific loss of Cys219 reactivity increases tumor growth and mortality in a xenograft model. Our findings establish a link between the precise oxidation of a host protein and tumorigenic signaling during bacterial infection and demonstrate the importance of oxidative post-translational modifications in tumor growth.

scholarly journals Structure/Function Analysis of the Hif1 Histone Chaperone in Saccharomyces cerevisiae

2021 ◽  
Author(s):  
Nora Saud Dannah
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Chromosome Segregation ◽  
Genome Stability ◽  
Function Analysis ◽  
Molecular Genetic ◽  
Histone Chaperone ◽  
Chromatin Assembly ◽  
Biological Processes ◽  
Genetic Approach ◽  
Yeast Saccharomyces Cerevisiae

Understanding the regulation of chromatin structure is a vital aspect of molecular biology regarding its influences on biological processes such as DNA replication, transcription (gene expression), DNA repair, chromosome segregation and recombination. In the budding yeast Saccharomyces cerevisiae, a histone chaperone called Hif1 has been found in the nuclei as having a functional role in chromatin assembly. Hif1 is a homolog of the human protein NASP that is involved in the maintenance of genome stability. Previously, Hif1 has been shown to physically interact with Hat1, Hat2 and H3/H4 to form the NuB4 complex directly involved in chromatin assembly. A molecular genetic approach was conducted to determine which domain of Hif1 is involved in the interaction with the HAT1 complex.

scholarly journals The Importance of ATM and ATR in Physcomitrella patens DNA Damage Repair, Development, and Gene Targeting

Genes ◽  
2020 ◽  
Vol 11 (7) ◽  
pp. 752
Author(s):  
Martin Martens ◽  
Ralf Horres ◽  
Edelgard Wendeler ◽  
Bernd Reiss
Keyword(s):  
Dna Damage ◽  
Gene Targeting ◽  
Genome Stability ◽  
Physcomitrella Patens ◽  
Dna Damage Repair ◽  
Transcriptional Response ◽  
Vegetative Development ◽  
Dsb Repair ◽  
Yeast Saccharomyces Cerevisiae ◽  
Damage Repair

Coordinated by ataxia-telangiectasia-mutated (ATM) and ATM and Rad3-related (ATR), two highly conserved kinases, DNA damage repair ensures genome integrity and survival in all organisms. The Arabidopsis thaliana (A. thaliana) orthologues are well characterized and exhibit typical mammalian characteristics. We mutated the Physcomitrella patens (P. patens) PpATM and PpATR genes by deleting functionally important domains using gene targeting. Both mutants showed growth abnormalities, indicating that these genes, particularly PpATR, are important for normal vegetative development. ATR was also required for repair of both direct and replication-coupled double-strand breaks (DSBs) and dominated the transcriptional response to direct DSBs, whereas ATM was far less important, as shown by assays assessing resistance to DSB induction and SuperSAGE-based transcriptomics focused on DNA damage repair genes. These characteristics differed significantly from the A. thaliana genes but resembled those in yeast (Saccharomyces cerevisiae). PpATR was not important for gene targeting, pointing to differences in the regulation of gene targeting and direct DSB repair. Our analysis suggests that ATM and ATR functions can be substantially diverged between plants. The differences in ATM and ATR reflect the differences in DSB repair pathway choices between A. thaliana and P. patens, suggesting that they represent adaptations to different demands for the maintenance of genome stability.

scholarly journals Mechanisms of RecQ helicases in pathways of DNA metabolism and maintenance of genomic stability

2006 ◽  
Vol 398 (3) ◽  
pp. 319-337 ◽  
Author(s):  
Sudha Sharma ◽  
Kevin M. Doherty ◽  
Robert M. Brosh
Keyword(s):  
Protein Interactions ◽  
Human Disease ◽  
Genome Stability ◽  
Molecular Motor ◽  
Genomic Stability ◽  
Premature Aging ◽  
Dna Metabolism ◽  
Dna Helicases ◽  
Recq Helicases ◽  
Hydrolysis Of

Helicases are molecular motor proteins that couple the hydrolysis of NTP to nucleic acid unwinding. The growing number of DNA helicases implicated in human disease suggests that their vital specialized roles in cellular pathways are important for the maintenance of genome stability. In particular, mutations in genes of the RecQ family of DNA helicases result in chromosomal instability diseases of premature aging and/or cancer predisposition. We will discuss the mechanisms of RecQ helicases in pathways of DNA metabolism. A review of RecQ helicases from bacteria to human reveals their importance in genomic stability by their participation with other proteins to resolve DNA replication and recombination intermediates. In the light of their known catalytic activities and protein interactions, proposed models for RecQ function will be summarized with an emphasis on how this distinct class of enzymes functions in chromosomal stability maintenance and prevention of human disease and cancer.

scholarly journals Reciprocal interaction between SIRT6 and APC/C regulates genomic stability

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Helin Wang ◽  
Kangze Feng ◽  
Qingtao Wang ◽  
Haiteng Deng
Keyword(s):  
Genome Stability ◽  
Chromosome Instability ◽  
Genomic Stability ◽  
Centrosome Amplification ◽  
Genome Integrity ◽  
Anaphase Promoting Complex ◽  
Mitotic Progression ◽  
Master Regulator ◽  
Reciprocal Interaction ◽  
Proteasome Pathway

AbstractSIRT6 is an NAD+-dependent deacetylase that plays an important role in mitosis fidelity and genome stability. In the present study, we found that SIRT6 overexpression leads to mitosis defects and aneuploidy. We identified SIRT6 as a novel substrate of anaphase-promoting complex/cyclosome (APC/C), which is a master regulator of mitosis. Both CDH1 and CDC20, co-activators of APC/C, mediated SIRT6 degradation via the ubiquitination-proteasome pathway. Reciprocally, SIRT6 also deacetylated CDH1 at lysine K135 and promoted its degradation, resulting in an increase in APC/C-CDH1-targeted substrates, dysfunction in centrosome amplification, and chromosome instability. Our findings demonstrate the importance of SIRT6 for genome integrity during mitotic progression and reveal how SIRT6 and APC/C cooperate to drive mitosis.

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