Causes of Telomere Shortening and Dysfunction

For many years, it was thought that telomere erosion and dysfunction were primarily a consequence of the “end replication problem”, or the inability of the replicative polymerase to completely duplicate linear chromosome ends. Work in my laboratory, however, changed this dogma. We contributed to a study demonstrating that double-stranded DNA breaks (DSBs), induced by drugs, endonucleases, or ionizing radiation, are, in fact, irreparable. As a consequence of genotoxic stresses that cause telomeric DSBs, telomeres become dysfunctional and rapidly trigger TDIS (Fumagalli et al. 2012 Nat Cell Biol) . In addition, we demonstrated that telomere dysfunction observed in tissue culture, as well as in tumor tissue, is primarily a result of telomeric DNA replication stresses triggered by BRCA2 deletion (contributed to (Badie et al. 2010 Nat Struct Mol Biol) ), drugs, oncogene expression (Suram et al. 2012 Embo J) , inactivation of the telomere specific DNA replication factor hStn1, or elevating the levels of reactive oxygen species (Boccardi et al. 2015 Aging Cell) . Our data, therefore, uncovered a novel and unexpected function of telomeres that of acting as a molecular trigger of cellular senescence in response to many stresses that place a cell at risk for malignant transformation (Figure 2). We are continuing to explore the causes for and mechanisms involved in telomere shortening, telomere attrition, and telomere dysfunction in human cells.