scholarly journals S. pombe DNA translocases Rrp1 and Rrp2 have distinct roles at centromeres and telomeres that ensure genome stability

2019 ◽  
Author(s):  
Anna Barg-Wojas ◽  
Kamila Schirmeisen ◽  
Jakub Muraszko ◽  
Karol Kramarz ◽  
Gabriela Baranowska ◽  
...  
Keyword(s):  
Schizosaccharomyces Pombe ◽  
Genome Stability ◽  
Genome Instability ◽  
Chromosome Instability ◽  
Telomere Maintenance ◽  
Nucleosome Dynamics ◽  
Dna Translocases ◽  
Telomere Function ◽  
And Function ◽  
Dna Translocase

ABSTRACTHomologous recombination (HR) is a DNA repair mechanism that ensures, together with heterochromatin machinery, the proper replication, structure and function of telomeres and centromeres that is essential for the maintenance of genome integrity. Schizosaccharomyces pombe Rrp1 and Rrp2 participate in HR and are orthologues of Saccharomyces cerevisiae Uls1, a SWI2/SNF2 DNA translocase and SUMO-Targeted Ubiquitin Ligase. We show that Rrp1 or Rrp2 upregulation leads to chromosome instability and growth defects. These phenotypes depend on putative DNA translocase activities of Rrp1 and Rrp2. Either Rrp1 or Rrp2 overproduction results in a reduction in global histone levels, suggesting that Rrp1 and Rrp2 may modulate nucleosome dynamics. In addition we show that Rrp2, but not Rrp1, acts at telomeres. We propose that this role depends on the previously described interaction between Rrp2 and Top2. We conclude that Rrp1 and Rrp2 have important roles for centromere and telomere function and maintenance, contributing to the preservation of genome stability during vegetative cell growth.SUMMARY STATEMENTSchizosaccharomyces pombe DNA translocases Rrp1 and Rrp2 modulate centromere and telomere maintenance pathways and dysregulation of their activity leads to genome instability.

scholarly journals Loss of Cdc13 causes genome instability by a deficiency in replication-dependent telomere capping

2019 ◽  
Author(s):  
Rachel E Langston ◽  
Dominic Palazzola ◽  
Erin Bonnell ◽  
Raymund J. Wellinger ◽  
Ted Weinert
Keyword(s):  
Homologous Recombination ◽  
Genome Stability ◽  
Genome Instability ◽  
Chromosome Instability ◽  
S Phase ◽  
Temperature Sensitive ◽  
End Joining ◽  
Telomere Capping ◽  
Non Homologous End Joining

AbstractIn budding yeast, Cdc13, Stn1, and Ten1 form a telomere binding heterotrimer dubbed CST. Here we investigate the role of Cdc13/CST in maintaining genome stability, using a Chr VII disome system that can generate recombinants, loss, and enigmatic unstable chromosomes. In cells expressing a temperature sensitive CDC13 allele, cdc13F684S, unstable chromosomes frequently arise due to problems in or near a telomere. Hence, when Cdc13 is defective, passage through S phase causes Exo1-dependent ssDNA and unstable chromosomes, which then are the source for whole chromosome instability events (e.g. recombinants, chromosome truncations, dicentrics, and/or loss). Specifically, genome instability arises from a defect in Cdc13’s replication-dependent telomere capping function, not Cdc13s putative post-replication telomere capping function. Furthermore, the unstable chromosomes form without involvement of homologous recombination nor non-homologous end joining. Our data suggest that a Cdc13/CST defect in semi-conservative replication near the telomere leads to ssDNA and unstable chromosomes, which then are lost or subject to complex rearrangements. This system defines a links between replication-dependent chromosome capping and genome stability in the form of unstable chromosomes.

scholarly journals The Relevance of G-Quadruplexes for DNA Repair

2021 ◽  
Vol 22 (22) ◽  
pp. 12599
Author(s):  
Rebecca Linke ◽  
Michaela Limmer ◽  
Stefan Juranek ◽  
Annkristin Heine ◽  
Katrin Paeschke
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genome Stability ◽  
Genome Instability ◽  
Genetic Disorders ◽  
Telomere Maintenance ◽  
Dna Structures ◽  
G4 Dna ◽  
G Quadruplex ◽  
Repair Pathways

DNA molecules can adopt a variety of alternative structures. Among these structures are G-quadruplex DNA structures (G4s), which support cellular function by affecting transcription, translation, and telomere maintenance. These structures can also induce genome instability by stalling replication, increasing DNA damage, and recombination events. G-quadruplex-driven genome instability is connected to tumorigenesis and other genetic disorders. In recent years, the connection between genome stability, DNA repair and G4 formation was further underlined by the identification of multiple DNA repair proteins and ligands which bind and stabilize said G4 structures to block specific DNA repair pathways. The relevance of G4s for different DNA repair pathways is complex and depends on the repair pathway itself. G4 structures can induce DNA damage and block efficient DNA repair, but they can also support the activity and function of certain repair pathways. In this review, we highlight the roles and consequences of G4 DNA structures for DNA repair initiation, processing, and the efficiency of various DNA repair pathways.

scholarly journals The Emerging Roles of TERRA in Telomere Maintenance and Genome Stability

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 246 ◽  
Author(s):  
Nicole Bettin ◽  
Claudio Oss Pegorar ◽  
Emilio Cusanelli
Keyword(s):  
Dna Replication ◽  
Genome Stability ◽  
Replicative Senescence ◽  
Chromosome Instability ◽  
Telomere Maintenance ◽  
Human Diseases ◽  
Specific Proteins ◽  
Telomere Biology ◽  
Telomere Structure ◽  
Chromosome End Protection

The finding that transcription occurs at chromosome ends has opened new fields of study on the roles of telomeric transcripts in chromosome end maintenance and genome stability. Indeed, the ends of chromosomes are required to be protected from activation of DNA damage response and DNA repair pathways. Chromosome end protection is achieved by the activity of specific proteins that associate with chromosome ends, forming telomeres. Telomeres need to be constantly maintained as they are in a heterochromatic state and fold into specific structures (T-loops), which may hamper DNA replication. In addition, in the absence of maintenance mechanisms, chromosome ends shorten at every cell division due to limitations in the DNA replication machinery, which is unable to fully replicate the extremities of chromosomes. Altered telomere structure or critically short chromosome ends generate dysfunctional telomeres, ultimately leading to replicative senescence or chromosome instability. Telomere biology is thus implicated in multiple human diseases, including cancer. Emerging evidence indicates that a class of long noncoding RNAs transcribed at telomeres, known as TERRA for “TElomeric Repeat-containing RNA,” actively participates in the mechanisms regulating telomere maintenance and chromosome end protection. However, the molecular details of TERRA activities remain to be elucidated. In this review, we discuss recent findings on the emerging roles of TERRA in telomere maintenance and genome stability and their implications in human diseases.

scholarly journals NBS1 interacts with HP1 to ensure genome integrity

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Giuseppe Bosso ◽  
Francesca Cipressa ◽  
Maria Lina Moroni ◽  
Rosa Pennisi ◽  
Jacopo Albanesi ◽  
...  
Keyword(s):  
Genome Stability ◽  
Cultured Cells ◽  
Chromosome Instability ◽  
Nijmegen Breakage Syndrome ◽  
Telomere Maintenance ◽  
Cellular Functions ◽  
Heterochromatin Protein 1 ◽  
Hypomorphic Mutation ◽  
Mrn Complex ◽  
Chromosome Integrity

AbstractHeterochromatin Protein 1 (HP1) and the Mre11-Rad50-Nbs1 (MRN) complex are conserved factors that play crucial role in genome stability and integrity. Despite their involvement in overlapping cellular functions, ranging from chromatin organization, telomere maintenance to DNA replication and repair, a tight functional relationship between HP1 and the MRN complex has never been elucidated. Here we show that the Drosophila HP1a protein binds to the MRN complex through its chromoshadow domain (CSD). In addition, loss of any of the MRN members reduces HP1a levels indicating that the MRN complex acts as regulator of HP1a stability. Moreover, overexpression of HP1a in nbs (but not in rad50 or mre11) mutant cells drastically reduces DNA damage associated with the loss of Nbs suggesting that HP1a and Nbs work in concert to maintain chromosome integrity in flies. We have also found that human HP1α and NBS1 interact with each other and that, similarly to Drosophila, siRNA-mediated inhibition of NBS1 reduces HP1α levels in human cultured cells. Surprisingly, fibroblasts from Nijmegen Breakage Syndrome (NBS) patients, carrying the 657del5 hypomorphic mutation in NBS1 and expressing the p26 and p70 NBS1 fragments, accumulate HP1α indicating that, differently from NBS1 knockout cells, the presence of truncated NBS1 extends HP1α turnover and/or promotes its stability. Remarkably, an siRNA-mediated reduction of HP1α in NBS fibroblasts decreases the hypersensitivity to irradiation, a characteristic of the NBS syndrome. Overall, our data provide an unanticipated evidence of a close interaction between HP1 and NBS1 that is essential for genome stability and point up HP1α as a potential target to counteract chromosome instability in NBS patient cells.

scholarly journals Polycomb Repression without Bristles: Facultative Heterochromatin and Genome Stability in Fungi

Genes ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. 638 ◽  
Author(s):  
John B. Ridenour ◽  
Mareike Möller ◽  
Michael Freitag
Keyword(s):  
Transcriptional Repression ◽  
Genome Stability ◽  
Genome Instability ◽  
Future Research ◽  
Genome Maintenance ◽  
Facultative Heterochromatin ◽  
H3k27 Methylation ◽  
Polycomb Repression ◽  
Fungal Genomes ◽  
And Function

Genome integrity is essential to maintain cellular function and viability. Consequently, genome instability is frequently associated with dysfunction in cells and associated with plant, animal, and human diseases. One consequence of relaxed genome maintenance that may be less appreciated is an increased potential for rapid adaptation to changing environments in all organisms. Here, we discuss evidence for the control and function of facultative heterochromatin, which is delineated by methylation of histone H3 lysine 27 (H3K27me) in many fungi. Aside from its relatively well understood role in transcriptional repression, accumulating evidence suggests that H3K27 methylation has an important role in controlling the balance between maintenance and generation of novelty in fungal genomes. We present a working model for a minimal repressive network mediated by H3K27 methylation in fungi and outline challenges for future research.

scholarly journals Exploring the Structures and Functions of Macromolecular SLX4-Nuclease Complexes in Genome Stability

2021 ◽  
Vol 12 ◽  
Author(s):  
Brandon J. Payliss ◽  
Ayushi Patel ◽  
Anneka C. Sheppard ◽  
Haley D. M. Wyatt
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Genome Stability ◽  
Genome Instability ◽  
Strand Break ◽  
Biochemical Properties ◽  
Strand Breaks ◽  
Dna Double Strand Break ◽  
Recent Developments ◽  
And Function

All organisms depend on the ability of cells to accurately duplicate and segregate DNA into progeny. However, DNA is frequently damaged by factors in the environment and from within cells. One of the most dangerous lesions is a DNA double-strand break. Unrepaired breaks are a major driving force for genome instability. Cells contain sophisticated DNA repair networks to counteract the harmful effects of genotoxic agents, thus safeguarding genome integrity. Homologous recombination is a high-fidelity, template-dependent DNA repair pathway essential for the accurate repair of DNA nicks, gaps and double-strand breaks. Accurate homologous recombination depends on the ability of cells to remove branched DNA structures that form during repair, which is achieved through the opposing actions of helicases and structure-selective endonucleases. This review focuses on a structure-selective endonuclease called SLX1-SLX4 and the macromolecular endonuclease complexes that assemble on the SLX4 scaffold. First, we discuss recent developments that illuminate the structure and biochemical properties of this somewhat atypical structure-selective endonuclease. We then summarize the multifaceted roles that are fulfilled by human SLX1-SLX4 and its associated endonucleases in homologous recombination and genome stability. Finally, we discuss recent work on SLX4-binding proteins that may represent integral components of these macromolecular nuclease complexes, emphasizing the structure and function of a protein called SLX4IP.

scholarly journals Loss of CBX2 induces genome instability and senescence-associated chromosomal rearrangements

2020 ◽  
Vol 219 (11) ◽  
Author(s):  
Claudia Baumann ◽  
Xiangyu Zhang ◽  
Rabindranath De La Fuente
Keyword(s):  
Dna Sequences ◽  
Genome Stability ◽  
Large Scale ◽  
Genome Instability ◽  
Chromosomal Rearrangements ◽  
Chromosome Instability ◽  
Nuclear Architecture ◽  
Polycomb Group ◽  
Polycomb Group Protein ◽  
Wide Range

The polycomb group protein CBX2 is an important epigenetic reader involved in cell proliferation and differentiation. While CBX2 overexpression occurs in a wide range of human tumors, targeted deletion results in homeotic transformation, proliferative defects, and premature senescence. However, its cellular function(s) and whether it plays a role in maintenance of genome stability remain to be determined. Here, we demonstrate that loss of CBX2 in mouse fibroblasts induces abnormal large-scale chromatin structure and chromosome instability. Integrative transcriptome analysis and ATAC-seq revealed a significant dysregulation of transcripts involved in DNA repair, chromocenter formation, and tumorigenesis in addition to changes in chromatin accessibility of genes involved in lateral sclerosis, basal transcription factors, and folate metabolism. Notably, Cbx2−/− cells exhibit prominent decondensation of satellite DNA sequences at metaphase and increased sister chromatid recombination events leading to rampant chromosome instability. The presence of extensive centromere and telomere defects suggests a prominent role for CBX2 in heterochromatin homeostasis and the regulation of nuclear architecture.

scholarly journals Schizosaccharomyces pombe DNA translocases Rrp1 and Rrp2 have distinct roles at centromeres and telomeres that ensure genome stability

2020 ◽  
Vol 133 (3) ◽  
pp. jcs230193 ◽  
Author(s):  
Anna Barg-Wojas ◽  
Jakub Muraszko ◽  
Karol Kramarz ◽  
Kamila Schirmeisen ◽  
Gabriela Baranowska ◽  
...  
Keyword(s):  
Schizosaccharomyces Pombe ◽  
Genome Stability ◽  
Dna Translocases

scholarly journals Telomere Signaling and Maintenance Pathways in Spermatozoa of Infertile Men Treated With Antioxidants: An in silico Approach Using Bioinformatic Analysis

2021 ◽  
Vol 9 ◽  
Author(s):  
Manesh Kumar Panner Selvam ◽  
Saradha Baskaran ◽  
Suresh C. Sikka
Keyword(s):  
Transcription Factors ◽  
Signaling Pathways ◽  
In Silico ◽  
Bioinformatic Analysis ◽  
Telomere Maintenance ◽  
Male Factor ◽  
Beneficial Effects ◽  
Sperm Proteins ◽  
Telomere Function ◽  
And Function

Telomere shortening is considered as a marker of cellular senescence and it is regulated by various signaling pathways. Sperm telomere appears to play important role in its longevity and function. Antioxidant intake has been known to prevent the shortening of telomere. In the management of male infertility, antioxidants are commonly used to counterbalance the seminal oxidative stress. It is important to understand how antioxidants treatment may modulate telomere signaling in sperm. In the current study, we have identified 377 sperm proteins regulated by antioxidants based on data mining of published literature. Bioinformatic analysis revealed involvement of 399 upstream regulators and 806 master regulators associated with differentially expressed sperm proteins. Furthermore, upstream regulator analysis indicated activation of kinases (EGFR and MAPK3) and transcription factors (CCNE1, H2AX, MYC, RB1, and TP53). Hence, it is evident that antioxidant supplementation activates molecules associated with telomere function in sperm. The outcome of this in silico study suggests that antioxidant therapy has beneficial effects on certain transcription factors and kinases associated with sperm telomere maintenance and associated signaling pathways that may play an important role in the management of male factor infertility.

scholarly journals Telomeres in Plants and Humans: Not So Different, Not So Similar

Cells ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 58 ◽  
Author(s):  
Petra Procházková Schrumpfová ◽  
Miloslava Fojtová ◽  
Jiří Fajkus
Keyword(s):  
Genome Stability ◽  
Genome Instability ◽  
Preventive Measure ◽  
Cell Types ◽  
Telomere Maintenance ◽  
Model Organisms ◽  
Multiple Model ◽  
Molecular Systems ◽  
Telomere Biology ◽  
Genotoxic Factors

Parallel research on multiple model organisms shows that while some principles of telomere biology are conserved among all eukaryotic kingdoms, we also find some deviations that reflect different evolutionary paths and life strategies, which may have diversified after the establishment of telomerase as a primary mechanism for telomere maintenance. Much more than animals, plants have to cope with environmental stressors, including genotoxic factors, due to their sessile lifestyle. This is, in principle, made possible by an increased capacity and efficiency of the molecular systems ensuring maintenance of genome stability, as well as a higher tolerance to genome instability. Furthermore, plant ontogenesis differs from that of animals in which tissue differentiation and telomerase silencing occur during early embryonic development, and the “telomere clock” in somatic cells may act as a preventive measure against carcinogenesis. This does not happen in plants, where growth and ontogenesis occur through the serial division of apical meristems consisting of a small group of stem cells that generate a linear series of cells, which differentiate into an array of cell types that make a shoot and root. Flowers, as generative plant organs, initiate from the shoot apical meristem in mature plants which is incompatible with the human-like developmental telomere shortening. In this review, we discuss differences between human and plant telomere biology and the implications for aging, genome stability, and cell and organism survival. In particular, we provide a comprehensive comparative overview of telomere proteins acting in humans and in Arabidopsis thaliana model plant, and discuss distinct epigenetic features of telomeric chromatin in these species.

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