TELOMERE LENGTH

The telomere length can either be shortened or elongated by an enzyme called telomerase after each cell
division. Interestingly, the shortest telomere is involved in controlling the ability of a cell to divide. Yet, its
dynamics remains elusive. We present here a stochastic approach where we model this dynamics using a
Markov jump process.We solve the forward Fokker-Planck equation to obtain the steady state distribution
and the statistical moments of telomere lengths. We focus specifically on the shortest one and we estimate
its length difference with the second shortest telomere. After extracting key parameters such as elongation
and shortening dynamics from experimental data, we compute the length of telomeres in yeast and obtain
as a possible prediction the minimum concentration of telomerase required to ensure a proper cell
division.

Within the area of forensics it would be of great help, both for identifications and in crime scene investigations, to be able to do an age estimate on humans simply on the basis of for instance bloodstains. Telomeres, that constitute the ends of human chromosomes, shorten with every cell division. Thus, telomere length might be used as an indicator of

Missegregation of chromosomes in meiosis, or nondisjunction, occurs relatively frequently in humans, and results in pregnancy loss. There is a correlation with advancing maternal age, but the cause of the dramatic increase of aneuploidy, and specifically trisomy (the presence of three copies of a chromosome rather then two), seen with age remains unknown. There is evidence to suggest that chronological age is less important than biological age for trisomy risk, and that regardless of their chronological age, some women are at a greater risk of having a trisomic pregnancy after having already experienced one. Several features of chromosomes are associated with aging, such as a decrease in telomere length, an increase in replication asynchrony at loci including centromeres, and an increase in somatic cell aneuploidy with increasing age. For some chromosomes (15 and 21) an association has also been observed between maternal age, reduced recombination along the chromosome, and risk for nondisjunction. In this project, I have investigated whether or not some women are predisposed to having a trisomic pregnancy. That is, can we predict who will have recurrent trisomy? After analyzing telomere length for an association, no significant decrease in length was seen for women experiencing recurrent trisomy when compared to control women. There was a trend, however, towards longer telomeres in women with a "good" reproductive history (children after 37 years of age) compared to women with a "poor" reproductive history (trisomy and/or recurrent trisomy). As well, although there was no significant increase in replication asynchrony in mothers of trisomy as a group, the younger mothers (<35 years old) of trisomies had increased replication asynchrony when compared to controls of the same age. The relationship between recombination and nondisjunction has been well established and my studies of chromosome 15 confirmed that decreased recombination is associated with meiosis I errors and increased recombination is associated with meiosis II errors. A family with an apparent inherited predisposition to missegregation of chromosome 21 seemed the ideal family in which to study possible genetic mechanisms of nondisjunction. Although nothing conclusive could be determined to be causing their segregation problems, a cryptic rearrangement involving the centromere of chromosome 21 is the most likely explanation. Finally, telomere length was not found to be shortened in children conceived through intracytoplasmic sperm injection (ICSI).

SUMMARY This years Nobel Prize in Physiology or Medicine is awarded to three scientists who have solved a major problem in biology: how the chromosomes can be copied in a complete way during cell divisions and how they are protected against degradation. The Nobel Laureates have shown that the solution is to be found in the ends of the chromosomes - the telomeres - and in an enzyme that forms them - telomerase. The long, thread-like DNA molecules that carry our genes are packed into chromosomes, the telomeres being the caps on their ends. Elizabeth Blackburn and Jack Szostak discovered that a unique DNA sequence in the telomeres protects the chromosomes from degradation. Carol Greider and Elizabeth Blackburn identified telomerase, the enzyme that makes telomere DNA. These discoveries explained how the ends of the chromosomes are protected by the telomeres and that they are built by telomerase. If the telomeres are shortened, cells age. Conversely, if telomerase activity is high, telo...

The Li-Fraumeni syndrome (LFS) is a rare, autosomal dominant disease caused by TP53 germline mutations. This study aimed to characterize the TP53 mutational spectrum in patients suspected to have LFS in Portugal and to evaluate the influence of the MDM2-SNP309 and TP53-72Arg variants and of telomere length on age of tumor onset. Probands were primarily selected using the classical LFS criteria (two cases) or the more sensitive Chompret Li-Fraumeni-like (LFL) criteria (13 cases), but 12 additional patients that did not comply with those LFS or LFL criteria were included in the analysis based on clinical suspicion (LFS suspects). Nine of the 27 probands (33.3%) presented germline TP53 mutations, two of them occurring de novo and two of them being novel. Three of the nine TP53 mutations were found in families that did not comply with any of the commonly used criteria for TP53 testing, leaving room to recommend the use of less stringent criteria. An association was found between the presence of the TP53-72Arg (but not the MDM2-SNP309) variant and earlier age of onset in TP53 carriers. A negative correlation between telomere length and age of cancer onset was found in patients with germline TP53 mutation, whereas no such correlation was found in controls or in patients with wild-type TP53.

Colorectal cancer (CRC) is a very frequently diagnosed pathological entity, registering an elevated incidence rate each year. CRC stems from both a genetic and an environmental background, exhibiting divergent molecular and biological phenotypes, and rendering its therapy, follow-up and prognosis a demanding task. Telomerase, a complex consisting of the catalytic protein human telomerase reverse transcriptase (hTERT) and the mRNA template hTERC, is related to the preservation of telomere length (TL). A wide range of studies suggest that hTERT also partakes in signalling pathways relevant to proliferation and apoptosis. Thus, the potent role of telomerase as a biomarker for CRC behaviour emerges as a reasonable inquiry.

Telomere dysfunction may result in chromosomal abnormalities, DNA damage responses, and even cancer. Early studies in lower organisms have helped to establish the crucial role of telomerase and telomeric proteins in maintaining telomere length and protecting telomere ends. In Oxytricha nova, telomere G-overhangs are protected by the TEBP-α/β heterodimer. Human telomeres contain duplex telomeric repeats with 3' single-stranded G-overhangs, and may fold into a t-loop structure that helps to shield them from being recognized as DNA breaks. Additionally, the TEBP-α homologue, POT1, which binds telomeric single-stranded DNA (ssDNA), associates with multiple telomeric proteins (for example, TPP1, TIN2, TRF1, TRF2 and RAP1) to form the six-protein telosome/shelterin and other subcomplexes. These telomeric protein complexes in turn interact with diverse pathways to form the telomere interactome for telomere maintenance. However, the mechanisms by which the POT1-containing telosome communicates with telomerase to regulate telomeres remain to be elucidated. Here we demonstrate that TPP1 is a putative mammalian homologue of TEBP-β and contains a predicted amino-terminal oligonucleotide/oligosaccharide binding (OB) fold. TPP1-POT1 association enhanced POT1 affinity for telomeric ssDNA. In addition, the TPP1 OB fold, as well as POT1-TPP1 binding, seemed critical for POT1-mediated telomere-length control and telomere-end protection in human cells. Disruption of POT1-TPP1 interaction by dominant negative TPP1 expression or RNA interference (RNAi) resulted in telomere-length alteration and DNA damage responses. Furthermore, we offer evidence that TPP1 associates with the telomerase in a TPP1-OB-fold-dependent manner, providing a physical link between telomerase and the telosome/shelterin complex. Our findings highlight the critical role of TPP1 in telomere maintenance, and support a yin-yang model in which TPP1 and POT1 function as a unit to protect human telomeres, by both positively and negatively regulating telomerase access to telomere DNA.

Mandibular hypoplasia, Deafness and Progeroid features with concomitant Lipodystrophy define a rare systemic disorder, named MDPL Syndrome, due to almost always a de novo variant in POLD1 gene, encoding the DNA polymerase δ. We report a MDPL female heterozygote for the recurrent p.Ser605del variant. In order to deepen the functional role of the in frame deletion affecting the polymerase catalytic site of the protein, cellular phenotype has been characterised. MDPL fibroblasts exhibit in vitro nuclear envelope anomalies, accumulation of prelamin A and presence of micronuclei. A decline of cell growth, cellular senescence and a blockage of proliferation in G0/G1 phase complete the aged cellular picture. The evaluation of the genomic instability reveals a delayed recovery from DNA induced-damage. Moreover, the rate of telomere shortening was greater in pathological cells, suggesting the telomere dysfunction as an emerging key feature in MDPL. Our results suggest an alteration in DNA replication/repair function of POLD1 as a primary pathogenetic cause of MDPL. The understanding of the mechanisms linking these cellular characteristics to the accelerated aging and to the wide spectrum of affected tissues and clinical symptoms in the MDPL patients may provide opportunities to develop therapeutic treatments for progeroid syndromes.

Telomeres are specialized nucleoprotein structures, which protect chromosome ends and have been implicated in the ageing process. Telomere shortening has been shown to contribute to a persistent DNA damage response (DDR) during replicative senescence, the irreversible loss of division potential of somatic cells. Similarly, persistent DDR foci can be found in stress-induced senescence, although their nature is not understood. Here we show, using immuno-fluorescent in situ hybridization and ChIP, that up to half of the DNA damage foci in stress-induced senescence are located at telomeres irrespective of telomerase activity. Moreover, live-cell imaging experiments reveal that all persistent foci are associated with telomeres. Finally, we report an age-dependent increase in frequencies of telomere-associated foci in gut and liver of mice, occurring irrespectively of telomere length. We conclude that telomeres are important targets for stress in vitro and in vivo and this has important c...

Results. Age-adjusted telomere length in AML patients was significantly reduced as compared to in matched controls, consisting of peripheral blood granulocytes from healthy individuals (0-90 years) (median: -2.5 TFU; p&lt;0.001). Patients with an aberrant karyotype had significant- ly shorter telomeres than did patients with a normal karyotype (median -3.0 vs. -2.3 TFU; p=0.03). The shortest telomeres were found in patients

Variation in telomere length is heritable and is currently considered a promising biomarker of susceptibility for neuropsychiatric disorders, particularly because of its association with memory function and hippocampal morphology. Here, we investigate telomere length in connection to familial risk and disease expression in bipolar disorder (BD). We used quantitative PCRs and a telomere-sequence to single-copy-gene-sequence ratio method to determine telomere length in genomic DNA extracted from buccal smears from 63 patients with BD, 74 first-degree relatives (49 relatives had no lifetime psychopathology and 25 had a non-BD mood disorder), and 80 unrelated healthy individuals. Participants also underwent magnetic resonance imaging to determine hippocampal volumes and cognitive assessment to evaluate episodic memory using the verbal paired associates test. Telomere length was shorter in psychiatrically well relatives (p=0.007) compared with unrelated healthy participants. Telomere len...