Telomere maintenance in interplay with DNA repair in pathogenesis and treatment of colorectal cancer

Mutagenesis ◽  
2020 ◽  
Vol 35 (3) ◽  
pp. 261-271 ◽  
Author(s):  
Kristyna Tomasova ◽  
Michal Kroupa ◽  
Asta Forsti ◽  
Pavel Vodicka ◽  
Ludmila Vodickova
Keyword(s):  
Colorectal Cancer ◽  
Dna Repair ◽  
Telomere Length ◽  
Replicative Senescence ◽  
Therapy Response ◽  
Cell Cycle Checkpoints ◽  
Telomere Maintenance ◽  
Telomere Attrition ◽  
Repair Mechanisms ◽  
Telomere Length Homeostasis

Abstract Colorectal cancer (CRC) continues to be one of the leading malignancies and causes of tumour-related deaths worldwide. Both impaired DNA repair mechanisms and disrupted telomere length homeostasis represent key culprits in CRC initiation, progression and prognosis. Mechanistically, altered DNA repair results in the accumulation of mutations in the genome and, ultimately, in genomic instability. DNA repair also determines the response to chemotherapeutics in CRC treatment, suggesting its utilisation in the prediction of therapy response and individual approach to patients. Telomere attrition resulting in replicative senescence, simultaneously by-passing cell cycle checkpoints, is a hallmark of malignant transformation of the cell. Telomerase is almost ubiquitous in advanced solid cancers, including CRC, and its expression is fundamental to cell immortalisation. Therefore, there is a persistent effort to develop therapeutics, which are telomerase-specific and gentle to non-malignant tissues. However, in practice, we are still at the level of clinical trials. The current state of knowledge and the route, which the research takes, gives us a positive perspective that the problem of molecular models of telomerase activation and telomere length stabilisation will finally be solved. We summarise the current literature herein, by pointing out the crosstalk between proteins involved in DNA repair and telomere length homeostasis in relation to CRC.

scholarly journals Platinum Complexes in Colorectal Cancer and Other Solid Tumors

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2073
Author(s):  
Beate Köberle ◽  
Sarah Schoch
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Cancer Cells ◽  
Cisplatin Resistance ◽  
Platinum Complexes ◽  
Dna Lesions ◽  
Dna Damage Signaling ◽  
Repair Mechanisms ◽  
P53 Inactivation

Cisplatin is one of the most commonly used drugs for the treatment of various solid neoplasms, including testicular, lung, ovarian, head and neck, and bladder cancers. Unfortunately, the therapeutic efficacy of cisplatin against colorectal cancer is poor. Various mechanisms appear to contribute to cisplatin resistance in cancer cells, including reduced drug accumulation, enhanced drug detoxification, modulation of DNA repair mechanisms, and finally alterations in cisplatin DNA damage signaling preventing apoptosis in cancer cells. Regarding colorectal cancer, defects in mismatch repair and altered p53-mediated DNA damage signaling are the main factors controlling the resistance phenotype. In particular, p53 inactivation appears to be associated with chemoresistance and poor prognosis. To overcome resistance in cancers, several strategies can be envisaged. Improved cisplatin analogues, which retain activity in resistant cancer, might be applied. Targeting p53-mediated DNA damage signaling provides another therapeutic strategy to circumvent cisplatin resistance. This review provides an overview on the DNA repair pathways involved in the processing of cisplatin damage and will describe signal transduction from cisplatin DNA lesions, with special attention given to colorectal cancer cells. Furthermore, examples for improved platinum compounds and biochemical modulators of cisplatin DNA damage signaling will be presented in the context of colon cancer therapy.

scholarly journals Recent Advances in Understanding Werner Syndrome

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1779 ◽  
Author(s):  
Raghavendra A. Shamanna ◽  
Deborah L. Croteau ◽  
Jong-Hyuk Lee ◽  
Vilhelm A. Bohr
Keyword(s):  
Dna Repair ◽  
Stem Cell ◽  
Genome Stability ◽  
Werner Syndrome ◽  
Genetic Disorder ◽  
Accelerated Aging ◽  
Nutrient Sensing ◽  
Telomere Maintenance ◽  
Telomere Attrition ◽  
Recent Advances

Aging, the universal phenomenon, affects human health and is the primary risk factor for major disease pathologies. Progeroid diseases, which mimic aging at an accelerated rate, have provided cues in understanding the hallmarks of aging. Mutations in DNA repair genes as well as in telomerase subunits are known to cause progeroid syndromes. Werner syndrome (WS), which is characterized by accelerated aging, is an autosomal-recessive genetic disorder. Hallmarks that define the aging process include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulation of nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. WS recapitulates these hallmarks of aging and shows increased incidence and early onset of specific cancers. Genome integrity and stability ensure the normal functioning of the cell and are mainly guarded by the DNA repair machinery and telomeres. WRN, being a RecQ helicase, protects genome stability by regulating DNA repair pathways and telomeres. Recent advances in WS research have elucidated WRN’s role in DNA repair pathway choice regulation, telomere maintenance, resolution of complex DNA structures, epigenetic regulation, and stem cell maintenance.

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 Obesity And Telomere Status In The Prognosis Of Colorectal Cancer Patients Submitted To Curative Intention Surgical Treatment

2020 ◽  
Author(s):  
Sergio García-Martínez ◽  
Daniel González-Gamo ◽  
Tamara Fernández-Marcelo ◽  
Sofía de la Serna ◽  
Inmaculada Serrano ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Surgical Treatment ◽  
Telomere Length ◽  
Clinical Outcomes ◽  
Published Data ◽  
Prognostic Impact ◽  
Telomere Attrition ◽  
Clinical Evolution ◽  
Obesity Status ◽  
The Impact

Abstract Background The risk of colorectal cancer (CRC) development has been related to telomere dysfunction and obesity. However, prognosis of patients affected by CRC has not clearly established considering both telomere attrition and obesity status. Previous published data highlights the importance of studying how obesity influences telomere function and its potential role as a predictor of prognosis in CRC. The aim of this study was to evaluate the impact of obesity and telomere status in the prognosis of patients affected by CRC and submitted to curative surgical treatment. Methods We performed a prospective study including 162 CRC patients submitted to curative surgical treatment. Samples were obtained from tumor and non-tumor tissues. Subjects were classified according to their Body Mass Index (BMI). Telomere status was established through telomere length and telomerase evaluation. Statistical analyses were performed using the SPSS software package version 22. Differences in two or more groups of study were calculated by parametric or non-parametric tests, depending on normality and homoscedasticity conditions of the variables. Prognosis was analyzed using the Kaplan-Meier method. The potential prognostic impact of the variables considered in this work jointly, was evaluated by Cox multivariate regression analyses. Results Patients with shorter telomeres, both in the tumor (median telomere length < 6.5 kb) and their non-tumor paired tissues (median telomere length < 7.1 kb), had the best clinical evolution, independently of the Dukes' stage of cancers (P = 0.025, for tumor samples; P = 0.003, for non-tumor samples). Telomere shortening was inversely associated with BMI in CRC patients. Also, subjects with a BMI > 31.85kg/m 2 showed the worse clinical outcomes. Of interest, the impact of BMI showed gender dependence, since only the group of men showed significant differences in CRC prognosis in relation to obesity status (P = 0.037). Conclusions Telomere length constitutes a useful biomarker to predict prognosis in CRC. Independently of BMI values, the better clinical evolution was associated with shorter telomeres. Obesity seems to have an impact on the clinical outcomes of CRC; however, the impact of BMI seems to be related to other factors such as gender.

scholarly journals Selective Elimination of Osteosarcoma Cell Lines with Short Telomeres by ATR Inhibitors

2020 ◽  
Author(s):  
Tomas Goncalves ◽  
Georgia Zoumpoulidou ◽  
Carlos Alvarez-Mendoza ◽  
Caterina Mancusi ◽  
Laura C. Collopy ◽  
...  
Keyword(s):  
Telomere Length ◽  
Cell Lines ◽  
Replicative Senescence ◽  
Telomere Maintenance ◽  
Osteosarcoma Cell ◽  
Cancer Evolution ◽  
Induced Apoptosis ◽  
Chromosome Bridges ◽  
Atr Kinase ◽  
Telomere Lengthening

AbstractTo avoid replicative senescence or telomere-induced apoptosis, cancers employ telomere maintenance mechanisms (TMMs) involving either the upregulation of telomerase or the acquisition of recombination-based alternative telomere lengthening (ALT). The choice of TMM may differentially influence cancer evolution and be exploitable in targeted therapies. Here, we examine TMMs in a panel of seventeen osteosarcoma-derived cell lines defining three separate groups according to TMM. Eight were ALT-positive, including the previously uncharacterised lines, KPD and LM7. ALT-negative cell lines were further classified into two groups according to their telomere length. HOS-MNNG, OHSN, SJSA-1, HAL, 143b and HOS displayed sub-normally short telomere length, while MG-63, MHM and HuO-3N1 displayed long telomeres. Importantly, sub-normally short telomeres were significantly associated with hypersensitivity to three different therapeutics targeting the ataxia telangiectasia and Rad3-related (ATR) kinase - AZD-6738/Ceralasertib, VE-822/Berzoserib and BAY-1895344 - compared to long telomeres, maintained via ALT or telomerase. Within 24 hours of ATR inhibition, cells with short but not long telomeres displayed chromosome bridges and underwent cell death, indicating a selective dependency on ATR for chromosome stability. Collectively, our work provides a resource to identify links between TMMs and drug sensitivity in osteosarcoma and indicates that telomere length predicts ATR-inhibitor sensitivity in cancer.

scholarly journals Increased Genome Instability and Telomere Length in the elg1-Deficient Saccharomyces cerevisiae Mutant Are Regulated by S-Phase Checkpoints

2004 ◽  
Vol 3 (6) ◽  
pp. 1557-1566 ◽  
Author(s):  
Soma Banerjee ◽  
Kyungjae Myung
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Damage ◽  
Dna Replication ◽  
Telomere Length ◽  
Genome Instability ◽  
Dna Recombination ◽  
Cell Cycle Checkpoints ◽  
Telomere Maintenance ◽  
Replication Checkpoint ◽  
Dna Replication Checkpoint

ABSTRACT Gross chromosomal rearrangements (GCRs) are frequently observed in cancer cells. Abnormalities in different DNA metabolism including DNA replication, cell cycle checkpoints, chromatin remodeling, telomere maintenance, and DNA recombination and repair cause GCRs in Saccharomyces cerevisiae. Recently, we used genome-wide screening to identify several genes the deletion of which increases GCRs in S. cerevisiae. Elg1, which was discovered during this screening, functions in DNA replication by participating in an alternative replication factor complex. Here we further characterize the GCR suppression mechanisms observed in the elg1Δ mutant strain in conjunction with the telomere maintenance role of Elg1. The elg1Δ mutation enhanced spontaneous DNA damage and resulted in GCR formation. However, DNA damage due to inactivation of Elg1 activates the intra-S checkpoints, which suppress further GCR formation. The intra-S checkpoints activated by the elg1Δ mutation also suppress GCR formation in strains defective in the DNA replication checkpoint. Lastly, the elg1Δ mutation increases telomere size independently of other previously known telomere maintenance proteins such as the telomerase inhibitor Pif1 or the telomere size regulator Rif1. The increase in telomere length caused by the elg1Δ mutation was suppressed by a defect in the DNA replication checkpoint, which suggests that DNA replication surveillance by Dpb11-Mec1/Tel1-Dun1 also has an important role in telomere length regulation.

scholarly journals Manipulation of DNA Repair Proficiency in Mouse Models of Colorectal Cancer

2016 ◽  
Vol 2016 ◽  
pp. 1-18 ◽  
Author(s):  
Michael A. Mcilhatton ◽  
Gregory P. Boivin ◽  
Joanna Groden
Keyword(s):  
Colorectal Cancer ◽  
Dna Repair ◽  
Mouse Models ◽  
Cancer Biology ◽  
Genetically Engineered ◽  
Biologically Relevant ◽  
Dna Repair Mechanisms ◽  
Genetically Engineered Mice ◽  
Repair Mechanisms

Technical and biological innovations have enabled the development of more sophisticated and focused murine models that increasingly recapitulate the complex pathologies of human diseases, in particular cancer. Mouse models provide excellentin vivosystems for deciphering the intricacies of cancer biology within the context of precise experimental settings. They present biologically relevant, adaptable platforms that are amenable to continual improvement and refinement. We discuss how recent advances in our understanding of tumorigenesis and the underlying deficiencies of DNA repair mechanisms that drive it have been informed by using genetically engineered mice to create defined, well-characterized models of human colorectal cancer. In particular, we focus on how mechanisms of DNA repair can be manipulated precisely to createin vivomodels whereby the underlying processes of tumorigenesis are accelerated or attenuated, dependent on the composite alleles carried by the mouse model. Such models have evolved to the stage where they now reflect the initiation and progression of sporadic cancers. The review is focused on mouse models of colorectal cancer and how insights from these models have been instrumental in shaping our understanding of the processes and potential therapies for this disease.

scholarly journals Age-related response to an acute innate immune challenge in mice: proteomics reveals a telomere maintenance-related cost

2018 ◽  
Vol 285 (1892) ◽  
pp. 20181877 ◽  
Author(s):  
François Criscuolo ◽  
Gabriele Sorci ◽  
Margaux Behaim-Delarbre ◽  
Sandrine Zahn ◽  
Bruno Faivre ◽  
...  
Keyword(s):  
Immune Response ◽  
Telomere Length ◽  
Innate Immune Response ◽  
Cellular Level ◽  
Innate Immune ◽  
Telomere Maintenance ◽  
Low Grade ◽  
Age Related ◽  
Repair Mechanisms ◽  
Low Grade Inflammation

Ageing is characterized by the impairment of the acute innate immune response and the upregulation of low-grade inflammation, i.e. inflammaging. At the cellular level, telomeres are considered as a marker of biological ageing as their length is progressively eroded in the absence of repair mechanisms. However, the link between telomeres and inflammaging remains underexplored. We aimed to identify proteins that are differentially expressed between age classes in response to an acute inflammatory challenge. We challenged young (two months) and old (12 months) C57BL/6 mice using bacterial lipopolysaccharide (LPS) and measured telomere length and proteomic profiles in splenocytes. In total, 233 out of the 1966 proteins we quantified differed among experimental groups. A hierarchical clustering analysis revealed that nine of those 233 proteins were differently expressed among the experimental groups. Young mice responded to LPS by increasing the expression of proteins involved in the innate immune response, and interestingly, in telomere length maintenance. However, this regulation was impaired at older ages. These results are in agreement with the assumption that the strength of selection declines with age, potentially explaining the maintenance of costly, dysregulated, immune responses at old age. We suggest that the immune response is competing with the telomere maintenance process, highlighting how telomeres reflect the ageing trade-off even in a species where telomere length is not related to lifespan.

The flow cytometric analysis of telomere length in antigen-specific CD8+ T cells during acute Epstein-Barr virus infection

Blood ◽  
2001 ◽  
Vol 97 (3) ◽  
pp. 700-707 ◽  
Author(s):  
Fiona J. Plunkett ◽  
Maria Vieira D. Soares ◽  
Nicola Annels ◽  
Andrew Hislop ◽  
Kamal Ivory ◽  
...  
Keyword(s):  
T Cells ◽  
Telomere Length ◽  
Cd8 T Cells ◽  
Epstein Barr Virus ◽  
Replicative Senescence ◽  
Telomere Maintenance ◽  
Epstein Barr Virus Infection ◽  
Telomere Shortening ◽  
Barr Virus ◽  
Epstein Barr

Abstract Acute infectious mononucleosis (AIM) induced by Epstein-Barr virus (EBV) infection is characterized by extensive expansion of antigen-specific CD8+ T cells. One potential consequence of this considerable proliferative activity is telomere shortening, which predisposes the EBV-specific cells to replicative senescence. To investigate this, a method was developed that enables the simultaneous identification of EBV specificity of the CD8+ T cells, using major histocompatibility complex (MHC) class I/peptide complexes, together with telomere length, which is determined by fluorescence in situ hybridization. Despite the considerable expansion, CD8+ EBV-specific T cells in patients with AIM maintain their telomere length relative to CD8+ T cells in normal individuals and relative to CD4+ T cells within the patients themselves and this is associated with the induction of the enzyme telomerase. In 4 patients who were studied up to 12 months after resolution of AIM, telomere lengths of EBV-specific CD8+ T cells were unchanged in 3 but shortened in one individual, who was studied only 5 months after initial onset of infection. Substantial telomere shortening in EBV-specific CD8+ T cells was observed in 3 patients who were studied between 15 months and 14 years after recovery from AIM. Thus, although telomerase activation may preserve the replicative potential of EBV-specific cells in AIM and after initial stages of disease resolution, the capacity of these cells to up-regulate this enzyme after restimulation by the persisting virus may dictate the extent of telomere maintenance in the memory CD8+ T-cell pool over time.

scholarly journals TERC Variants Associated with Short Leukocyte Telomeres: Implication of Higher Early Life Leukocyte Telomere Attrition as Assessed by the Blood-and-Muscle Model

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1360
Author(s):  
Simon Toupance ◽  
Maria G. Stathopoulou ◽  
Alexandros M. Petrelis ◽  
Vesna Gorenjak ◽  
Carlos Labat ◽  
...  
Keyword(s):  
Telomere Length ◽  
Early Life ◽  
Telomere Maintenance ◽  
Muscle Model ◽  
Mendelian Randomisation ◽  
Atherosclerotic Cardiovascular Disease ◽  
Nucleotide Polymorphisms ◽  
Telomere Attrition ◽  
Adult Age

Short leukocyte telomere length (LTL) is associated with atherosclerotic cardiovascular disease (ASCVD). Mendelian randomisation studies, using single nucleotide polymorphisms (SNPs) associated with short LTL, infer a causal role of LTL in ASCVD. Recent results, using the blood-and-muscle model, indicate that higher early life LTL attrition, as estimated by the ratio between LTL and skeletal muscle telomere length (MTL), rather than short LTL at conception, as estimated by MTL, should be responsible of the ASCVD-LTL connection. We combined LTL and MTL measurements and SNPs profiling in 402 individuals to determine if 15 SNPs classically described as associated with short LTL at adult age were rather responsible for higher LTL attrition during early life than for shorter LTL at birth. Two of these SNPs (rs12696304 and rs10936599) were associated with LTL in our cohort (p = 0.027 and p = 0.025, respectively). These SNPs, both located on the TERC gene, were associated with the LTL/MTL ratio (p = 0.007 and p = 0.037, respectively), but not with MTL (p = 0.78 and p = 0.32 respectively). These results suggest that SNPs located on genes coding for telomere maintenance proteins may contribute to a higher LTL attrition during the highly replicative first years of life and have an impact later on the development of ASCVD.

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