The telomere is a special functional complex at the end of linear eukaryotic chromosomes, consisting of tandem repeat DNA sequences and associated proteins. It is essential for maintaining the integrity and stability of linear eukaryotic genomes. Telomere length regulation and maintenance contribute to normal human cellular aging and human diseases. The synthesis of telomeres is mainly achieved by the cellular reverse transcriptase telomerase, an RNA-dependent DNA polymerase that adds telomeric DNA to telomeres. Expression of telomerase is usually required for cell immortalization and long-term tumor growth. In humans, telomerase activity is tightly regulated during development and oncogenesis. The modulation of telomerase activity may therefore have important implications in antiaging and anticancer therapy. This review describes the currently known components of the telomerase complex and attempts to provide an update on the molecular mechanisms of human telomerase regulation

No abstract

In mammals, molecular mechanisms and factors involved in the tight regulation of telomerase expression and activity are still largely undefined. In this study, we provide evidence for a role of estrogens and their receptors in the transcriptional regulation of hTERT, the catalytic subunit of human telomerase and, consequently, in the activation of the enzyme. Through a computer analysis of the hTERT 5-flanking sequences, we identified a putative estrogen response element (ERE) which was capable of binding in vitro human estrogen receptor ␣ (ER␣). In vivo DNA footprinting revealed specific modifications of the ERE region in ER␣-positive but not ER␣-negative cells upon treatment with 17␤-estradiol (E2), indicative of estrogen-dependent chromatin remodelling. In the presence of E2, transient expression of ER␣ but not ER␤ remarkably increased hTERT promoter activity, and mutation of the ERE significantly reduced this effect. No telomerase activity was detected in human ovary epithelial cells grown in the absence of E2, but the addition of the hormone induced the enzyme within 3 h of treatment. The expression of hTERT mRNA and protein was induced in parallel with enzymatic activity. This prompt estrogen modulation of telomerase activity substantiates estrogen-dependent transcriptional regulation of the hTERT gene. The identification of hTERT as a target of estrogens represents a novel finding which advances the understanding of telomerase regulation in hormone-dependent cells and has implications for a potential role of hormones in their senescence and malignant conversion.Most human somatic cells do not express telomerase, the ribonucleoprotein that elongates telomeric DNA, or its catalytic protein, hTERT, which is limiting for enzyme activity (33). In humans, telomerase is regulated in a tissue-specific manner during development (42); the enzyme is present in early embryogenesis but is repressed upon cell differentiation in somatic tissues (27,42). Loss of enzymatic activity is accompanied by loss of the full-length transcript of hTERT and/or by the appearance of alternatively spliced transcripts that are unlikely to encode functional proteins (21, 42). In the adult, telomerase persists only in germ line cells and in progenitor cells of somatic tissues with self-renewing potential, in agreement with the requirement for the enzyme for sustained cell proliferation (16). How hTERT silencing is achieved and which factors contribute to this process are presently unknown, although the regulation of hTERT expression appears to be primarily at the transcriptional level (42). An understanding of the molecular mechanisms underlying the regulation of telomerase activity might allow the modulation of telomerase expression and, consequently, of cell life span (4, 43), with important potential therapeutic applications in aging and malignancy.Several lines of evidence suggest that sex steroid hormones may be good candidates as physiological regulators of hTERT expression. Recent findings are consistent with the hypothesis that te...

The fetal fraction was affected by fetal aneuploidy, maternal BMI, and the number of gestation. Maternal preexisting of hypertension appeared to reduce fetal fraction.

A proper DNA damage response (DDR) is essential to maintain genome integrity and prevent tumorigenesis. DNA double-strand breaks (DSBs) are the most toxic DNA lesion and their repair is orchestrated by the ATM kinase. ATM is activated via the MRE11–RAD50–NBS1 (MRN) complex along with its autophosphorylation at S1981 and acetylation at K3106. Activated ATM rapidly phosphorylates a vast number of substrates in local chromatin, providing a scaffold for the assembly of higher-order complexes that can repair damaged DNA. While reversible ubiquitination has an important role in the DSB response, modification of the newly identified ubiquitin-like protein ubiquitin-fold modifier 1 and the function of UFMylation in the DDR is largely unknown. Here, we found that MRE11 is UFMylated on K282 and this UFMylation is required for the MRN complex formation under unperturbed conditions and DSB-induced optimal ATM activation, homologous recombination-mediated repair and genome integrity. A pathogenic mutation MRE11(G285C) identified in uterine endometrioid carcinoma exhibited a similar cellular phenotype as the UFMylation-defective mutant MRE11(K282R). Taken together, MRE11 UFMylation promotes ATM activation, DSB repair and genome stability, and potentially serves as a therapeutic target.