Human Telomeres and Recombination
thesisposted on 13.03.2013, 11:22 by Alberto Hidalgo Bravo
Telomeres are DNA-protein complexes that help protecting the end of linear chromosomes. They consist of repetitive DNA, in mammals the repeat unit is the hexanucleotide TTAGGG, these repeats span 5-20 kb. Under normal conditions in somatic cells, telomeres get shorter with every population doubling until they reach a critical length and then, the cell enters a checkpoint called senescence or M1 where it stops dividing. If the cell escapes senescence and continues dividing with further telomere shortening, it reaches a second checkpoint called crisis or M2. Crisis is characterized by telomere dysfunction leading to genomic instability that can end with cell death. However, some cells achieve to maintain telomere length by activating a telomere maintenance mechanism (TMM). The presence of a TMM is a hallmark of cancer cells. Two TMM have been described in human cells, one is the through the enzyme telomerase, which is active in 85% of cancers, and the second is a homologous recombination (HR) based mechanism called Alternative Lengthening of Telomeres (ALT) active in 15% of cancers. The evidence that the ALT pathway relies in HR was the observation that sequences can be copied from one telomere to another in ALT+ but not in telomerase+ cells and that several genes involved in HR are necessary for ALT progression. The ALT pathway is not the only event involving HR at telomeres. It has been shown that the human herpesvirus 6 (HHV-6) can integrate into human telomeres. Interestingly, HHV-6 possesses perfect telomeric repeats within its genome. The proposed mechanism for integration if through HR between the telomeric repeats present in the virus with the human telomere repeats. The aim of this work is to unravel the molecular mechanism underlying the ALT pathway and HHV-6 integration. The data obtained will contribute to the understanding of HR in human telomeres.