Telomerase enzymatic component hTERT shortens long telomeres in human cells

Telomere lengths are tightly regulated within a narrow range in normal human cells. Previous studies have extensively focused on how short telomeres are extended and have demonstrated that telomerase plays a central role in elongating short telomeres. However, much about the molecular mechanisms of regulating excessively long telomeres is unknown. In this report, we demonstrated that the telomerase enzymatic component, hTERT, plays a dual role in the regulation of telomere length. It shortens excessively long telomeres and elongates short telomeres simultaneously in one cell, maintaining the optimal telomere length at each chromosomal end for efficient protection. This novel hTERT-mediated telomere-shortening mechanism not only exists in cancer cells, but also in primary human cells. The hTERT-mediated telomere shortening requires hTERT’s enzymatic activity, but the telomerase RNA component, hTR, is not involved in that process. We found that expression of hTERT increases telomeric circular DNA formation, suggesting that telomere homologous recombination is involved in the telomere-shortening process. We further demonstrated that shelterin protein TPP1 interacts with hTERT and recruits hTERT onto the telomeres, suggesting that TPP1 might be involved in regulation of telomere shortening. This study reveals a novel function of hTERT in telomere length regulation and adds a new element to the current molecular model of telomere length maintenance

Integrative Approach Detected Association between Genetic Variants of microRNA Binding Sites of TLRs Pathway Genes and OSCC Susceptibility in Chinese Han Population

<div><p>Oral squamous cell carcinoma (OSCC) is a leading malignancy worldwide; the overall 5-year survival rate is approximately 50%. A variety of proteins in Toll-like receptors (TLRs) pathway have been related with the risk of OSCC. However, the influence of genetic variations in TLRs pathway genes on OSCC susceptibility is unclear. Previous studies mainly focused on the coding region of genes, while the UTR region remains unstudied. In the current study, a bioinformatics approach was performed to select candidate single nucleotide polymorphisms (SNPs) on microRNA binding sites of TLRs pathway genes related with OSCC. After screening 90 OSCC related TLRs pathway genes, 16 SNPs were selected for genotyping. We found that rs5030486, the polymorphisms on 3′ UTR of <i>TRAF6</i>, was significantly associated with OSCC risk. AG genotype of <i>TRAF6</i> was strongly associated with a decreased risk of OSCC (OR = 0.252; 95% CI = 0.106, 0.598; p = 0.001). In addition, AG genotype was also related with a reduced risk of OSCC progression both in univariable analysis (HR = 0.303, 95% CI = 0.092, 0.995) and multivariable analysis (HR = 0.272, 95% CI = 0.082, 0.903). Furthermore, after detecting the mRNA expression level of <i>TRAF6</i> in 24 OSCC patients, we found that <i>TRAF6</i> expression level was significantly different between patients carrying different genotypes at locus rs5030486 (p = 0.013), indicating that rs5030486 of <i>TRAF6</i> might contribute to OSCC risk by altering <i>TRAF6</i> expression level. In general, these data indicated that SNP rs5030486 could be a potential bio-marker for OSCC risk and our results might provide new insights into the association of polymorphisms within the non-coding area of genes with cancers.</p></div

Kaplan–Meier curves of progression-free survival time of OSCC patients carrying AA and AG genotypes of rs5030486 on <i>TRAF6</i>.

<p>Kaplan–Meier curves of progression-free survival time of OSCC patients carrying AA and AG genotypes of rs5030486 on <i>TRAF6</i>.</p

The information about six predicted polymorphisms.

<p>The information about six predicted polymorphisms.</p

Association between SNPs and the risk of OSCC.

<p>OR, odds ratio; CI, confidence interval.</p><p>The bold numbers mean the <i>p</i>-value is less than 0.05.</p

Aberrant expression and localization of the RAP1 shelterin protein contribute to age-related phenotypes.

Short telomeres induce a DNA damage response (DDR) that evokes apoptosis and senescence in human cells. An extant question is the contribution of telomere dysfunction-induced DDR to the phenotypes observed in aging and telomere biology disorders. One candidate is RAP1, a telomere-associated protein that also controls transcription at extratelomeric regions. To distinguish these roles, we generated a knockin mouse carrying a mutated Rap1, which was incapable of binding telomeres and did not result in eroded telomeres or a DDR. Primary Rap1 knockin embryonic fibroblasts showed decreased RAP1 expression and re-localization away from telomeres, with an increased cytosolic distribution akin to that observed in human fibroblasts undergoing telomere erosion. Rap1 knockin mice were viable, but exhibited transcriptomic alterations, proinflammatory cytokine/chemokine signaling, reduced lifespan, and decreased healthspan with increased body weight/fasting blood glucose levels, spontaneous tumor incidence, and behavioral deficits. Taken together, our data present mechanisms distinct from telomere-induced DDR that underlie age-related phenotypes

The overall schematic diagram of this study.

<p>The overall schematic diagram of this study.</p