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The science of ageing
Published in Michael Parker, Charlie James, Fundamentals for Cosmetic Practice, 2022
The Hayflick Limit is determined in no small part by protective caps on the end of chromosomes called telomeres. Telomeres are repeating nucleotide sequences which function to shield the ends of chromosomes from accidental deletion or binding to adjacent chromosomes, and they themselves are protected by protein complexes, known as shelterin proteins, as well as the RNA, which itself encodes the telomere. By having these long base sequences at the ends of DNA strands, it means they can effectively act as a buffer to enzymes which may replicated the DNA erroneously. In vertebrates, the nucleotide sequences are AGGGTT with a complementary TCCCAA on the opposite DNA sequence. Overhanging this is a single-stranded sequence of TTAGGG nucleotides which repeat approximately 2,500 times in humans. At birth we have approximately 11,000 base pairs making up the telomere on the ends of our chromosomes, yet this decreases to approximately 4,000 in old age. The rate of decline in the length of a telomere is greater in men and is likely one of the many reasons men age faster and die younger than women.
Dyskeratosis Congenita
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Telomeres are coated by shelterin complex (telomere end protection/capping), an assembly of six associated proteins: (i) telomeric repeat binding factor 1 (TRF1; also known as TERF1) and (ii) TRF2 (also known as TERF2), (iii) TRF1-interacting nuclear factor 2 (TIN2), (iv) protection of telomeres (POT1), (v) TIN2-interacting protein 1 (TPP1) (also known as TINT1, PToP, and PIP1), and (vi) repressor/activator protein 1 (RAP1). RAP1 in mammals is involved in subtelomeric gene silencing and transcriptional regulation, and it also acts as an essential modulator of the nuclear factor-κB (NF-κB)-mediated pathway. Shelterin components play multiple roles in maintaining telomere length homeostasis by forming the T loops, preventing DNA damage response activation (DDRA), and recruiting the telomerase complex and modulating its activity. Although the regulation of shelterin components in stem cells and during nuclear reprogramming is still unexplored, some recent evidence suggests shelterin components as key factors in “stemness.” Some cases of premature aging in human syndromes have been linked to shelterin mutations, such as in TRF1, TRF2, and TIN2 (also known as TINF2).
Haematology
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
DC is a clinically and genetically heterogeneous disorder, showing X-linked, autosomal dominant and recessive inheritence. Several genes have been shown to cause DC, all of whom have clear roles in teleomere maintenence. These include the telomerase complex (TERC, TERT, DKC1, NHP2, NOP10), the shelterin complex (TINF2), telomerase trafficking (TCAB1) and the telomere capping complex (CTC1).
The biology and management of dyskeratosis congenita and related disorders of telomeres
Published in Expert Review of Hematology, 2022
Hemanth Tummala, Amanda Walne, Inderjeet Dokal
Heterozygous variants in TINF2, which encode a component (TIN2) of the shelterin complex, were identified in 2008 in one subtype of AD-DC. The shelterin complex is composed of six proteins: TRF1 (telomeric-repeat binding protein 1), TRF2 (telomeric-repeat binding protein 2), TIN2 (TRF1-interacting nuclear factor 2), RAP1 (TERF2-interacting protein), TPP1 (TIN2-interacting protein 1), and POT1 (protection of telomeres) [18]. TRF1, TRF2, and POT1 of the shelterin complex (Figure 3) bind directly to the telomeric DNA: TRF1 and TRF2 bind to double stranded DNA and POT1 to the single stranded DNA overhang. The shelterin complex has several functions: it determines the structure of the telomeric terminus, generates t-loops and controls the synthesis of telomeric DNA by telomerase. Without shelterin, telomeres are not protected and chromosome ends are incorrectly processed by the DNA repair pathways. The composition and interactions of components of the shelterin complex are highly ordered with TIN2 (encoded by TINF2) occupying a central role.
Patented therapeutic approaches targeting LRP/LR for cancer treatment
Published in Expert Opinion on Therapeutic Patents, 2019
Leila Vania, Gavin Morris, Tyrone C Otgaar, Monique J Bignoux, Martin Bernert, Jessica Burns, Anne Gabathuse, Elvira Singh, Eloise Ferreira, Stefan F T Weiss
There is an increasing amount of evidence to suggest that telomerase is also implicated in cancer and aging by actions beyond its function in maintaining telomeres [87]. It is known that the inhibition of telomerase, and the resultant loss of telomere maintenance, results in apoptosis. This effective the loss of telomerase activity causes progressive telomere shortening and leads to the inactivation of the telomere capping function of the shelterin complex, eventually leading to cell death [88]. The catalytic subunit of telomerase, hTERT, has been found to play a role in regulating apoptosis, independent of telomere maintenance and telomerase activity. It has been demonstrated both in vitro and in vivo, that there is a direct association between TERT and an increased resistance to apoptosis [89]. In addition, hTERT overexpression has been found to make cells more resistant to apoptosis [90]. The study showed that telomerase expression did not prevent stress-induced senescence in normal human fibroblasts, but rather protected the cells from apoptosis [90]. Moreover, a recent study has shown that downregulating hTERT through RNA silencing, activated Bax, which triggered a mitochondrial cell death pathway [91]. Furthermore, this did not occur as a result of telomerase inhibition, as there was no telomere erosion, ultimately suggesting a role of TERT in preventing apoptosis [91].
Role of telomeric RAP1 in radiation sensitivity modulation and its interaction with CSC marker KLF4 in colorectal cancer
Published in International Journal of Radiation Biology, 2020
Kumari Anuja, Madhabananda Kar, Amit Roy Chowdhury, Gauri Shankar, Swatishree Padhi, Souvick Roy, Yusuf Akhter, Arabinda Kumar Rath, Birendranath Banerjee
Telomere is DNA protein complex composed of a variable number of tandem repeats TTAGGG sequences and associated proteins, plays a crucial role in maintaining the genomic integrity (Greider and Blackburn 1989; de Lange 2005; Stohr et al. 2010; Sfeir and de Lange 2012). Telomere function is maintained by shelterin complex (TRF1, TRF2, RAP1, TIN2, POT1, and TPP1) and telomerase reverse transcriptase (TERT) that extends telomeres. These proteins are regulated by reprograming stem cell factors which might serve as a potential target in cancer treatment, especially in radiotherapy (Wong et al. 2010; Akiyama et al. 2013; Shim et al. 2014).