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 DNA–protein crosslink proteases in genome stability

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Annamaria Ruggiano ◽  
Kristijan Ramadan
Keyword(s):  
Dna Replication ◽  
Cancer Therapy ◽  
Genome Stability ◽  
Dna Lesions ◽  
Protein Component ◽  
Human Diseases ◽  
Direct Link ◽  
The Past ◽  
Protein Crosslinks ◽  
Bulky Dna Lesions

AbstractProteins covalently attached to DNA, also known as DNA–protein crosslinks (DPCs), are common and bulky DNA lesions that interfere with DNA replication, repair, transcription and recombination. Research in the past several years indicates that cells possess dedicated enzymes, known as DPC proteases, which digest the protein component of a DPC. Interestingly, DPC proteases also play a role in proteolysis beside DPC repair, such as in degrading excess histones during DNA replication or controlling DNA replication checkpoints. Here, we discuss the importance of DPC proteases in DNA replication, genome stability and their direct link to human diseases and cancer therapy.

scholarly journals Trf1 Is Not Required for Proliferation or Functional Telomere Maintenance in Chicken DT40 Cells

2009 ◽  
Vol 20 (10) ◽  
pp. 2563-2571 ◽  
Author(s):  
Carol Cooley ◽  
Katie M. Baird ◽  
Virginie Faure ◽  
Thomas Wenner ◽  
Jillian L. Stewart ◽  
...  
Keyword(s):  
Genome Stability ◽  
De Novo ◽  
Telomere Maintenance ◽  
Clonal Variation ◽  
Fish Analysis ◽  
Double Stranded Dna ◽  
Late Passage ◽  
Telomere Structure ◽  
Dt40 Cells ◽  
Novel Exon

The telomere end-protection complex prevents the ends of linear eukaryotic chromosomes from degradation or inappropriate DNA repair. The homodimeric double-stranded DNA-binding protein, Trf1, is a component of this complex and is essential for mouse embryonic development. To define the requirement for Trf1 in somatic cells, we deleted Trf1 in chicken DT40 cells by gene targeting. Trf1-deficient cells proliferated as rapidly as control cells and showed telomeric localization of Trf2, Rap1, and Pot1. Telomeric G-strand overhang lengths were increased in late-passage Trf1-deficient cells, although telomere lengths were unaffected by Trf1 deficiency, as determined by denaturing Southern and quantitative FISH analysis. Although we observed some clonal variation in terminal telomere fragment lengths, this did not correlate with cellular Trf1 levels. Trf1 was not required for telomere seeding, indicating that de novo telomere formation can proceed without Trf1. The Pin2 isoform and a novel exon 4, 5–deleted isoform localized to telomeres in Trf1-deficient cells. Trf1-deficient cells were sensitive to DNA damage induced by ionizing radiation. Our data demonstrate that chicken DT40 B cells do not require Trf1 for functional telomere structure and suggest that Trf1 may have additional, nontelomeric roles involved in maintaining genome stability.

scholarly journals Increase in lamin B1 promotes telomere instability by disrupting the shelterin complex in human cells

2021 ◽  
Author(s):  
Gaëlle Pennarun ◽  
Julien Picotto ◽  
Laure Etourneaud ◽  
Anna-Rita Redavid ◽  
Anaïs Certain ◽  
...  
Keyword(s):  
Dna Replication ◽  
Nuclear Periphery ◽  
Human Cells ◽  
Telomere Maintenance ◽  
Regulation Of Transcription ◽  
Lamin B1 ◽  
Shelterin Complex ◽  
Dna Replication And Repair ◽  
Specific Proteins ◽  
New Interactions

Abstract Telomere maintenance is essential to preserve genomic stability and involves telomere-specific proteins, DNA replication and repair proteins. Lamins are key components of the nuclear envelope and play numerous roles, including maintenance of the nuclear integrity, regulation of transcription, and DNA replication. Elevated levels of lamin B1, one of the major lamins, have been observed in some human pathologies and several cancers. Yet, the effect of lamin B1 dysregulation on telomere maintenance remains unknown. Here, we unveil that lamin B1 overexpression drives telomere instability through the disruption of the shelterin complex. Indeed, lamin B1 dysregulation leads to an increase in telomere dysfunction-induced foci, telomeric fusions and telomere losses in human cells. Telomere aberrations were preceded by mislocalizations of TRF2 and its binding partner RAP1. Interestingly, we identified new interactions between lamin B1 and these shelterin proteins, which are strongly enhanced at the nuclear periphery upon lamin B1 overexpression. Importantly, chromosomal fusions induced by lamin B1 in excess were rescued by TRF2 overexpression. These data indicated that lamin B1 overexpression triggers telomere instability through a mislocalization of TRF2. Altogether our results point to lamin B1 as a new interacting partner of TRF2, that is involved in telomere stability.

scholarly journals Evaluations of short telomere risk-associated single nucleotide polymorphisms in telomerase reverse transcriptase gene on telomere length maintenance

2019 ◽  
Author(s):  
Jialin Xu ◽  
Matthew A. Trudeau ◽  
Andrew J. Sandford ◽  
Judy M.Y. Wong
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Reverse Transcriptase ◽  
Telomere Length ◽  
Replicative Senescence ◽  
Telomere Maintenance ◽  
Telomerase Reverse Transcriptase ◽  
Nucleotide Polymorphisms ◽  
Primary Cells ◽  
Single Nucleotide ◽  
Telomere Biology

ABSTRACTTelomere biology disorders (TBDs) refer to a spectrum of tissue degenerative disorders caused by genetic mutations in telomere biology genes. Most patients with TBDs suffer from telomere maintenance defects secondary to telomerase deficiency. While the highly penetrant mutations in the telomerase reverse transcriptase (TERT) gene that drive disease onset and progression of TBDs are relatively rare, there exist several single nucleotide polymorphisms (SNPs) in TERT that have been linked to various diseases in the TBD spectrum. In this study, we investigated the biochemical properties of five TERT variants. In an ex vivo cell model, we found that primary human fibroblasts expressing nonsynonymous TERT SNPs had comparable cell growth kinetics to primary cells expressing WT-TERT, while a parallel vector control expressing-cell line entered replicative senescence. At the molecular level, primary cells expressing the minor alleles of two of the five TERT variants (A279T, ΔE441) had replication-dependent loss of telomere length. In an in vitro primer extension assay, these two variants showed reduced telomerase nucleotide addition processivity. Together, our data suggested that selective, common TERT variants could be revealed to harbour telomere maintenance defects, leading to a plausible explanation for their observed associations to telomere biology disorders.

scholarly journals Evolution of telomere maintenance and tumour suppressor mechanisms across mammals

2018 ◽  
Vol 373 (1741) ◽  
pp. 20160443 ◽  
Author(s):  
Xiao Tian ◽  
Katherine Doerig ◽  
Rosa Park ◽  
Alice Can Ran Qin ◽  
Chaewon Hwang ◽  
...  
Keyword(s):  
Replicative Senescence ◽  
Mammalian Species ◽  
Telomerase Activity ◽  
Tumour Suppressor ◽  
Telomere Maintenance ◽  
Large Species ◽  
Increased Risk ◽  
Telomere Biology ◽  
Risk Of Cancer ◽  
Species Lifespan

Mammalian species differ dramatically in telomere biology. Species larger than 5–10 kg repress somatic telomerase activity and have shorter telomeres, leading to replicative senescence. It has been proposed that evolution of replicative senescence in large-bodied species is an anti-tumour mechanism counteracting increased risk of cancer due to increased cell numbers. By contrast, small-bodied species express high telomerase activity and have longer telomeres. To counteract cancer risk due to longer lifespan, long-lived small-bodied species evolved additional telomere-independent tumour suppressor mechanisms. Here, we tested the connection between telomere biology and tumorigenesis by analysing the propensity of fibroblasts from 18 rodent species to form tumours. We found a negative correlation between species lifespan and anchorage-independent growth. Small-bodied species required inactivation of Rb and/or p53 and expression of oncogenic H-Ras to form tumours. Large-bodied species displayed a continuum of phenotypes requiring additional genetic ‘hits’ for malignant transformation. Based on these data we refine the model of the evolution of tumour suppressor mechanisms and telomeres. We propose that two different strategies evolved in small and large species because small-bodied species cannot tolerate small tumours that form prior to activation of the telomere barrier, and must instead use telomere-independent strategies that act earlier, at the hyperplasia stage. This article is part of the theme issue ‘Understanding diversity in telomere dynamics’.

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 Mgs1 function at G-quadruplex structures during DNA replication

2020 ◽  
Author(s):  
Katrin Paeschke ◽  
Peter Burkovics
Keyword(s):  
Dna Replication ◽  
Genome Stability ◽  
Mechanistic Model ◽  
Regulation Of Gene Expression ◽  
Telomere Maintenance ◽  
Dna Structures ◽  
Genomic Deletions ◽  
G Quadruplex

AbstractThe coordinated action of DNA polymerases and DNA helicases is essential at genomic sites that are hard to replicate. Among these are sites that harbour G-quadruplex DNA structures (G4). G4s are stable alternative DNA structures, which have been implicated to be involved in important cellular processes like the regulation of gene expression or telomere maintenance. G4 structures were shown to hinder replication fork progression and cause genomic deletions, mutations and recombination events. Many helicases unwind G4 structures and preserve genome stability, but a detailed understanding of G4 replication and the re-start of stalled replication forks around formed G4 structures is not clear, yet. In our recent study, we identified that Mgs1 preferentially binds to G4 DNA structures in vitro and is associated with putative G4-forming chromosomal regions in vivo. Mgs1 binding to G4 motifs in vivo is partially dependent on the helicase Pif1. Pif1 is the major G4-unwinding helicase in S. cerevisiae. In the absence of Mgs1, we determined elevated gross chromosomal rearrangement (GCR) rates in yeast, similar to Pif1 deletion. Here, we highlight the recent findings and set these into context with a new mechanistic model. We propose that Mgs1's functions support DNA replication at G4-forming regions.

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 Direct quantification of the translocation activities of Saccharomyces cerevisiae Pif1 helicase

2019 ◽  
Vol 47 (14) ◽  
pp. 7494-7501
Author(s):  
Chen Lu ◽  
Shimin Le ◽  
Jin Chen ◽  
Alicia K Byrd ◽  
Daniela Rhodes ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Replication ◽  
Genome Stability ◽  
Dna Helicase ◽  
Telomere Maintenance ◽  
The Other ◽  
Biological Processes ◽  
Helicase Activity ◽  
Pif1 Helicase ◽  
Direct Quantification

AbstractSaccharomyces cerevisiae Pif1 (ScPif1) is known as an ATP-dependent DNA helicase that plays critical roles in a number of important biological processes such as DNA replication, telomere maintenance and genome stability maintenance. Besides its DNA helicase activity, ScPif1 is also known as a single-stranded DNA (ssDNA) translocase, while how ScPif1 translocates on ssDNA is unclear. Here, by measuring the translocation activity of individual ScPif1 molecules on ssDNA extended by mechanical force, we identified two distinct types of ssDNA translocation. In one type, ScPif1 moves along the ssDNA track with a rate of ∼140 nt/s in 100 μM ATP, whereas in the other type, ScPif1 is immobilized to a fixed location of ssDNA and generates ssDNA loops against force. Between the two, the mobile translocation is the major form at nanomolar ScPif1 concentrations although patrolling becomes more frequent at micromolar concentrations. Together, our results suggest that ScPif1 translocates on extended ssDNA in two distinct modes, primarily in a ‘mobile’ manner.

scholarly journals Emerging functions of Fanconi anemia genes in replication fork protection pathways

2020 ◽  
Vol 29 (R2) ◽  
pp. R158-R164 ◽  
Author(s):  
Arun Mouli Kolinjivadi ◽  
Wayne Crismani ◽  
Joanne Ngeow
Keyword(s):  
Dna Replication ◽  
Fanconi Anemia ◽  
Replication Fork ◽  
Genome Stability ◽  
Chromosome Instability ◽  
Replication Stress ◽  
Short Review ◽  
Gene Products ◽  
Dna Double Strand Breaks ◽  
Variants Of Unknown Significance

Abstract Germline mutations in Fanconi anemia (FA) genes predispose to chromosome instability syndromes, such as FA and cancers. FA gene products have traditionally been studied for their role in interstrand cross link (ICL) repair. A fraction of FA gene products are classical homologous recombination (HR) factors that are involved in repairing DNA double-strand breaks (DSBs) in an error-free manner. Emerging evidence suggests that, independent of ICL and HR repair, FA genes protect DNA replication forks in the presence of replication stress. Therefore, understanding the precise function of FA genes and their role in promoting genome stability in response to DNA replication stress is crucial for diagnosing FA and FA-associated cancers. Moreover, molecular understanding of the FA pathway will greatly help to establish proper functional assays for variants of unknown significance (VUS), often encountered in clinics. In this short review, we discuss the recently uncovered molecular details of FA genes in replication fork protection pathways. Finally, we examine how novel FA variants predispose to FA and cancer, due to defective replication fork protection activity.

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