Glossary
Displacement (D) loop: DNA structure
The end of linear chromosomes is formed by a special heterochromatic structure, known as the telomere, that protects chromosome ends from degradation and DNA repair and recombination activities. Therefore, telomeres are essential to ensure chromosome stability 1, 2, 3, 4, 5, 6, 7, 8. Mammalian telomeres comprise several kilobases (i.e., 10–15 kb in humans and 25–50 kb in mice) of tandem TTAGGG DNA repeats [9]. Telomeres are characterized by the presence of a 30–400-nucleotide 3′ overhang of the
During each cell division cycle, telomeres shorten because of the incomplete replication of linear DNA molecules by conventional DNA polymerases, which is called the ‘end-replication problem’ 48, 49. The molecular basis of this DNA loss is that DNA polymerases require a 3′-OH group as the site for nucleotide addition and therefore cannot initiate DNA synthesis de novo. Semiconservative replication relies on the coordinated action of DNA-dependent DNA polymerase complexes to synthesize the
The CST complex comprises the proteins CTC1, STN1, and TEN1, all of which contain putative OB-fold domains involved in binding single-stranded DNA and promoting protein interactions 71, 72. Human CTC1 and STN1 were initially purified as Polα-associated stimulatory factors (AAFs), which stimulate template binding and enzyme processivity 73, 74. The CST complex has structural and functional similarities to Replication Protein A (RPA) and has a role in DNA replication both at telomeres and
A conserved feature of telomeres is the 3′ overhang comprising G-rich repeats that protrudes beyond the complementary C-rich telomeric repeat strand. The lengths of G-strand overhangs in mammalian cells vary between 30 and 400 nucleotides and they are present at both ends of each chromosome 10, 11. DNA processing to generate the G overhangs occurs regardless of whether a cell expresses telomerase and occurs in telomeres replicated by both leading and lagging strand synthesis. The terminal
Telomere maintenance is a multistep, highly regulated process in which many different factors are involved, including epigenetic events. Replication of telomeric DNA involves passage of a replication fork along the telomeric DNA duplex, where the conventional replication machinery encounters challenges arising from topological interference by the T loop and the formation of DNA secondary structures such as G quadruplexes. After replication, generation of the G overhang occurs through 5′-end
Research in the Blasco laboratory is funded by the Spanish Ministry of Economy and Competitiveness Projects SAF2008-05384 and CSD2007-00017, the European Union FP7 Projects 2007-A-201630 (GENICA) and 2007-A-200950 (TELOMARKER), the European Research Council (ERC) Project TEL STEM CELL (GA#232854), the Körber Foundation, the AXA Research Fund, and Fundación Botín and Fundación Lilly (Spain). F.B. is ICREA Academia, Generalitat de Catalunya, Spain. Glossary Displacement (D) loop: DNA structure
TIN2 interact with both TRF1 and TRF2, and then it connects to TPP1, which in turn binds to POT and improves complex stabilization [40–42]. Since DNA polymerase is unable to synthesize the latest Okazaki fragments and cannot wholly replicate the 3′end of the chromosome, which is known as “end replication problem” and exonuclease activity degrades the end of the chromosome, for these reasons, the length of the telomere becomes shorter with each replication [43–45]. The end replication problem causes the telomere to act as an internal clock that determines the number of cell divisions [46,47].