Regulation of Antigenic Variation by Trypanosoma brucei Telomere Proteins Depends on Their Unique DNA Binding Activities

Trypanosoma brucei causes human African trypanosomiasis and regularly switches its major surface antigen, Variant Surface Glycoprotein (VSG), to evade the host immune response. Such antigenic variation is a key pathogenesis mechanism that enables T. brucei to establish long-term infections. VSG is expressed exclusively from subtelomere loci in a strictly monoallelic manner, and DNA recombination is an important VSG switching pathway. The integrity of telomere and subtelomere structure, maintained by multiple telomere proteins, is essential for T. brucei viability and for regulating the monoallelic VSG expression and VSG switching. Here we will focus on T. brucei TRF and RAP1, two telomere proteins with unique nucleic acid binding activities, and summarize their functions in telomere integrity and stability, VSG switching, and monoallelic VSG expression. Targeting the unique features of TbTRF and TbRAP1′s nucleic acid binding activities to perturb the integrity of telomere structure and disrupt VSG monoallelic expression may serve as potential therapeutic strategy against T. brucei.

Telomeric and Sub-Telomeric Structure and Implications in Fungal Opportunistic Pathogens

Telomeres are long non-coding regions found at the ends of eukaryotic linear chromosomes. Although they have traditionally been associated with the protection of linear DNA ends to avoid gene losses during each round of DNA replication, recent studies have demonstrated that the role of these sequences and their adjacent regions go beyond just protecting chromosomal ends. Regions nearby to telomeric sequences have now been identified as having increased variability in the form of duplications and rearrangements that result in new functional abilities and biodiversity. Furthermore, unique fungal telomeric and chromatin structures have now extended clinical capabilities and understanding of pathogenicity levels. In this review, telomere structure, as well as functional implications, will be examined in opportunistic fungal pathogens, including Aspergillus fumigatus, Candida albicans, Candida glabrata, and Pneumocystis jirovecii.

The SUN1-SPDYA interaction plays an essential role in meiosis prophase I

Chromosomes pair and synapse with their homologous partners to segregate correctly at the first meiotic division. Association of telomeres with the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex composed of SUN1 and KASH5 enables telomere-led chromosome movements and telomere bouquet formation, facilitating precise pairwise alignment of homologs. Here, we identify a direct interaction between SUN1 and Speedy A (SPDYA) and determine the crystal structure of human SUN1-SPDYA-CDK2 ternary complex. Analysis of meiosis prophase I process in SPDYA-binding-deficient SUN1 mutant mice reveals that the SUN1-SPDYA interaction is required for the telomere-LINC complex connection and the assembly of a ring-shaped telomere supramolecular architecture at the nuclear envelope, which is critical for efficient homologous pairing and synapsis. Overall, our results provide structural insights into meiotic telomere structure that is essential for meiotic prophase I progression.

The Power of Stress: The Telo-Hormesis Hypothesis

Adaptative response to stress is a strategy conserved across evolution to promote survival. In this context, the groundbreaking findings of Miroslav Radman on the adaptative value of changing mutation rates opened new avenues in our understanding of stress response. Inspired by this work, we explore here the putative beneficial effects of changing the ends of eukaryotic chromosomes, the telomeres, in response to stress. We first summarize basic principles in telomere biology and then describe how various types of stress can alter telomere structure and functions. Finally, we discuss the hypothesis of stress-induced telomere signaling with hormetic effects.

Trypanosoma brucei PolIE suppresses telomere recombination

Telomeres are essential for genome integrity and stability. In T. brucei that causes human African trypanosomiasis, the telomere structure and telomere proteins also influence the virulence of the parasite, as its major surface antigen involved in the host immune evasion is expressed exclusively from loci immediately upstream of the telomere repeats. However, telomere maintenance mechanisms are still unclear except that telomerase-mediated telomere synthesis is a major player. We now identify PolIE as an intrinsic telomere complex component. We find that depletion of PolIE leads to an increased amount of telomere/subtelomere DNA damage, an elevated rate of antigenic variation, and an increased amount of telomere T-circles and C-circles, indicating that PolIE suppresses telomere recombination and helps maintain telomere integrity. In addition, we observe much longer telomere G-rich 3 prime overhangs in PolIE-depleted cells, which is not dependent on telomerase. Furthermore, the level of telomere DNA synthesis is slightly increased in PolIE-depleted cells, which is dependent on telomerase. Therefore, we identify PolIE as a major player for telomere maintenance in T. brucei.

TELOMERE BIOLOGY: TELOMERE STRUCTURE, FUNCTION AND RELATED DISEASES

Telomere is the special heterochromatin structure which caps the end of eukaryotic chromosome and ensures the faithful replication of genetic materials. It also provides the protection against DNA damage signals and ensures the genome integrity and stability. Telomerase complete its task by its unique nucleoprotein structure. Here in this paper detail about nucleoprotein structure and their function is included. Robustness of function of telomere across cell cycle is guaranteed by the interaction between telomere and its interacting proteins. Recent findings regarding telomere biology and cancer are also included in this paper. KEY WORDS: Telomere, DNA damage, cell cycle, cancer

Chromatin modifiers and recombination factors promote a telomere fold-back structure, that is lost during replicative senescence

Telomeres adopt a lariat conformation and hence, engage in long and short distance intra-chromosome interactions. Budding yeast telomeres were proposed to fold back into subtelomeric regions, but a robust assay to quantitatively characterize this structure has been lacking. Therefore, it is not well understood how the interactions between telomeres and non-telomeric regions are established and regulated. We employ a telomeric chromosome conformation capture (Telo-3C) approach to directly analyze telomere folding and its maintenance in S. cerevisiae. We identify the histone modifiers Sir2, Sin3 and Set2 as critical regulators for telomere folding, which suggests that a distinct telomeric chromatin environment is a major requirement for the folding of yeast telomeres. We demonstrate that telomeres are not folded when cells enter replicative senescence, which occurs independently of short telomere length. Indeed, Sir2, Sin3 and Set2 protein levels are decreased during senescence and their absence may thereby prevent telomere folding. Additionally, we show that the homologous recombination machinery, including the Rad51 and Rad52 proteins, as well as the checkpoint component Rad53 are essential for establishing the telomere fold-back structure. This study outlines a method to interrogate telomere-subtelomere interactions at a single unmodified yeast telomere. Using this method, we provide insights into how the spatial arrangement of the chromosome end structure is established and demonstrate that telomere folding is compromised throughout replicative senescence.Author summaryTelomeres are the protective caps of chromosome ends and prevent the activation of a local DNA damage response. In many organisms, telomeres engage in a loop-like structure which may provide an additional layer of end protection. As we still lack insight into the regulation of the folded telomere structure, we used budding yeast to establish a method to measure telomere folding and then study the genetic requirements for its establishment. We found that cells require the homologous recombination machinery as well as components of the DNA damage checkpoint to successfully establish a folded telomere. Through the deletion of telomerase in budding yeast, we investigated how telomere folding was regulated during replicative senescence, a process that occurs in the majority of telomerase negative human cells. During senescence, telomeres gradually shorten and erode until cells stop dividing which is a potent tumor suppressor and prevents unscheduled growth of potential cancer cells. We found, that the folded telomere structure is compromised as part of the cellular senescence response, but not due to telomere shortening per se. We think, that an altered telomeric chromatin environment during senescence is important to maintain an open state – which may be important for signaling or for repair.

The Response to DNA Damage at Telomeric Repeats and Its Consequences for Telomere Function

Telomeric repeats, coated by the shelterin complex, prevent inappropriate activation of the DNA damage response at the ends of linear chromosomes. Shelterin has evolved distinct solutions to protect telomeres from different aspects of the DNA damage response. These solutions include formation of t-loops, which can sequester the chromosome terminus from DNA-end sensors and inhibition of key steps in the DNA damage response. While blocking the DNA damage response at chromosome ends, telomeres make wide use of many of its players to deal with exogenous damage and replication stress. This review focuses on the interplay between the end-protection functions and the response to DNA damage occurring inside the telomeric repeats, as well as on the consequences that telomere damage has on telomere structure and function.