Unit:
Κατεύθυνση Εφαρμογές της Βιολογίας στην ΙατρικήLibrary of the School of Science
Author:
Cherdyntseva Veroniki-Charalampia
Supervisors info:
Δημήτριος Στραβοπόδης, Επίκουρος Καθηγητής Τμήματος Βιολογίας, ΕΚΠΑ
Σαράντης Γκάγκος, Ερευνητής Β΄, Ίδρυμα Ιατροβιολογικών Ερευνών της Ακαδημίας Αθηνών
Ισιδώρα Παπασιδέρη, Καθηγήτρια Τμήματος Βιολογίας, ΕΚΠΑ
Original Title:
Διερεύνηση τελομερικών μηχανισμών επιδιόρθωσης του DNA
Translated title:
Investigating the role of DNA repair mechanisms at chromosome termini
Summary:
The Alternative Lengthening of Telomeres (ALT) is a homology-mediated pathway of telomere elongation that sustains continuous cell growth in 10-15% of human cancers. Among others, ALT is characterized by the presence of highly heterogenous telomere lengths, extrachromosomal telomeric repeats, as well as increased frequency of telomere-associated promyelocytic leukemia protein bodies (APBs). The mechanism underlying ALT in human neoplasia is a conservative DNA replication process, orchestrated by Break-induced replication (BIR). EXD2 is a largely uncharacterized MRN-interacting exonuclease that facilitates homology-mediated DNA repair. In the ALT human osteosarcoma cell line U2OS, EXD2 forms distinct nuclear foci which frequently colocalize with the telomere specific protein TRF2, the telomeric repeats per se, and the APBs. Moreover, EXD2 functions as an exonuclease at the ALT telomeres, and suppresses classical homology-mediated recombination (c-HR). The absence of EXD2 increases the number of telomere free ends and reduces the overall length of telomeres. In addition, it appears that EXD2 suppresses the biogenesis of C-circles, as well as the production of APBs. Despite chromosome breakage in cells lacking EXD2, the rates of chromosome end-fusions are minimal, suggesting an important role of EXD2 in telomeric alt-EJ. Indeed, high rates of chromosome end-fusions -induced upon expression of a dominant negative TRF2ΔΒ/ΔM form of TRF2-, are rescued in ALT cells lacking EXD2. The above results bring new insight into the complex interactions between different repair machineries and the recombinatorial telomere elongation of ALT telomeres, highlighting EXD2 as a potential target for future therapeutic strategies to combat cancer.
Main subject category:
Science
Keywords:
Telomeres, Alternative lengthening of telomeres, ALT, EXD2, DNA repair, Genomic instability, Cancer
Number of references:
119
