Telomerase Repairs Collapsed Replication Forks at Telomeres

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Impact of Gln94Glu mutation on the structure and function of protection of telomere 1, a cause of cutaneous familial melanoma

Abstract

Protection of telomere 1 (POT1) is a key component of shelterin complex, essential for maintaining telomere length and its regulation. It consists of N-terminal domain (residues 1–299), which interacts with telomeric ssDNA, and the C-terminal domain (residues 320–634) that binds to the tripeptidyl-peptidase I (TPP1). A large number of naturally occurring mutations in the POT1 gene are associated with glioma, cardiac angiosarcoma and cutaneous familial melanoma (FM). In particular, Q94E mutation disrupts the interaction of POT1 with telomeric DNA which subsequently enhances telomere uncapping and elongation and promotes the development of cutaneous familial melanoma. To understand the underlying mechanism of familial melanoma developed by Q94E-mutation, we have performed extensive structure analysis of WT and mutant protein followed by molecular dynamics simulations. Q94E mutation causes a dramatic change in the structure and stability of POT1 protein. A considerable decrease in the flexibility, fluctuation and solvent accessibility of Q94E was observed in comparison to the WT, indicating overall destabilization of protein. Essential dynamics and Anisotropic Network Mode analysis have quantified a significant change in direction and magnitude of conformational motion in Q94E mutant compared to WT. A significant loss of frustration due to Q94E mutation was also observed. Our findings indicate the loss of protein stability and dynamics of POT1 protein by Q94E mutation may be associated with the familial melanoma. Abbreviations ANM anisotropic network mode

ED essential dynamics

FM familial melanoma

MD molecular dynamics

POT1 protection of telomere 1

Rg radius of gyration

RMSD root-mean-square deviation

RMSF root-mean-square fluctuations

SASA solvent accessible surface area

SIFT sorting Intolerant from Tolerant

TPP1 tripeptidyl-peptidase I

WT wild type

Communicated by Ramaswamy H. Sarma     

Initiation of telomere‐mediated chromosomal rearrangements in cancer

Telomeres are the ends of chromosomes and protect them from degradation and fusion. As such, their stability is required for normal cellular function. Telomere dysfunction is found often at the origin of cellular transformation and contributes to the onset of genomic instability, a hallmark of cancer cells. In this article, I discuss current data and concepts on telomere‐mediated chromosomal rearrangements in cancer. J. Cell. Biochem. 109: 1095–1102, 2010. © 2010 Wiley‐Liss, Inc.     

Paternal exposure to exercise and/or caffeine and alcohol modify offspring behavioral and pathophysiological recovery from repetitive mild traumatic brain injury in adolescence

Only recently has the scope of parental research expanded to include the paternal sphere with epidemiological studies implicating stress, nutrition and alcohol consumption in the neurobiological and behavioral characteristics of offspring. This study was designed to determine if paternal exposure to caffeine, alcohol and exercise prior to conception would improve or exacerbate offspring recovery from adolescent repetitive mild traumatic brain injury (RmTBI). Sires received 7 weeks of standard drinking water, or caffeine and ethanol and were housed in regular cages or cages with running wheels, prior to being mated to control females. At postnatal day 40, offspring were administered RmTBI or sham injuries and were assessed for post concussive symptomology. Post-mortem quantitative real-time polymerase chain reaction (qRT-PCR) was used to assess gene expression in the prefrontal cortex (PFC), nucleus accumbens (NAc) and changes in telomere length. Additionally, enzyme-linked immunosorbent assay (ELISA's) were run on serum to detect levels of cytokines, chemokines and sex hormones. Paternal experience did not improve or exacerbate RmTBI behavioral outcomes. However, female and male offspring displayed unique responses to RmTBI and paternal experience, resulting in changes in physical, behavioral and molecular outcomes. Injury and paternal exercise modified changes in female offspring, whereas male offspring were affected by paternal exercise, caffeine and alcohol treatment. Additionally, paternal experience and RmTBI modified expression of many genes in the PFC, NAc, telomere length and levels of sex hormones. Although further exploration is required to understand the heterogeneity that exists in disease risk and resiliency, this study provides corroborating evidence that paternal experiences prior to conception influences offspring development.     

Nestling telomere length does not predict longevity,but covaries with adult body size in wild barn swallows

Telomere length and dynamics are increasingly scrutinized as ultimate determinants of performance, including age-dependent mortality and fecundity. Few studies have investigated longevity in relation to telomere length (TL) in the wild and none has analysed longevity in relation to TL soon after hatching, despite the fact that telomere shortening may mostly occur early in life. We show that TL in nestling barn swallows (Hirundo rustica) in the wild does not predict longevity. However, TL positively covaries with body size, suggesting that individuals with large TL can afford to grow larger without paying the cost of reduced TL, and/or that benign rearing conditions ensure both large body size and low rates of telomere shortening. Overall, our study hints at a role of TL in developmental processes, but also indicates a need for further analyses to assess the expectation that TL in young individuals predicts longevity in the wild.     

RNA-DNA hybrids prevent resection at dysfunctional telomeres

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Telomere dynamics may link stress exposure and ageing across generations

Although exposure to stressors is known to increase disease susceptibility and accelerate ageing, evidence is accumulating that these effects can span more than one generation. Stressors experienced by parents have been reported to negatively influence the longevity of their offspring and even grand offspring. The mechanisms underlying these long-term, cross-generational effects are still poorly understood, but we argue here that telomere dynamics are likely to play an important role. In this review, we begin by surveying the current connections between stress and telomere dynamics. We then lay out the evidence that exposure to stressors in the parental generation influences telomere dynamics in offspring and potentially subsequent generations. We focus on evidence in mammalian and avian studies and highlight several promising areas where our understanding is incomplete and future investigations are critically needed. Understanding the mechanisms that link stress exposure across generations requires interdisciplinary studies and is essential to both the biomedical community seeking to understand how early adversity impacts health span and evolutionary ecologists interested in how changing environmental conditions are likely to influence age-structured population dynamics.