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Yikang Rong, Ph.D.
Telomeres cap chromosome ends so that they are not recognized as double strand breaks (DSBs). Uncapped telomeres, like DSBs, activate DNA damage checkpoints that can lead to apoptosis or senescence. Uncapped telomeres, like DSBs, can be subject to promiscuous DNA repair leading to genome instability, a hallmark of cancer. Therefore, proper telomere capping is of paramount importance to genome maintenance. The long-term goal of our research is to understand how eukaryotic cells distinguish telomeres from DSBs.
In the fruit fly, Drosophila, telomere identity is determined epigenetically. Although Drosophila telomeres consist of retro-transposons, they are neither necessary nor sufficient for capping. In particular, terminally deleted chromosomes that lack these transposons are stable, hence capped, for many generations. Without this sequence component, Drosophila telomeres most resemble DSBs, and thus represent a simpler system for the study of end capping. Furthermore, specialized yeast and plant cells can be immortalized in the absence of telomeric repeats with protected telomeres, suggesting that these repeats are not necessary for capping in telomerase-maintained organisms under certain conditions. These results suggest that sequence-independent capping might operate in all eukaryotes.
Despite using a telomerase-independent mechanism for elongating telomeres, Drosophila employ highly conserved factors to regulate capping. We showed that the ATM and ATR checkpoint kinases, along with the Mre11-Rad50-Nbs (MRN) complex and the ATRIP protein respectively, control redundant pathways for capping regulation that are conserved in other organisms. Several other proteins serving capping function in Drosophila have homologs in other organisms: HP1, UbcD1, Woc and we recently identified a novel function for the H2A.Z histone variant in capping regulation. Due to the high degree of conservation in these proteins, information gained from studies in Drosophila is likely applicable to other organisms. In addition, telomerase-independent capping mechanism similar to those in Drosophila might operate in normal human somatic cells and certain cancer cells that do not produce telomerase.
Our research is aimed at: (1) identifying the molecules and molecular events required for telomere protection. We are currently conducting structural and functional characterization of capping components from two complexes; (2) understanding the differences in chromatin structure of capped versus uncapped telomeres. We have initiated a study of the chromatin structures of a molecularly defined telomere and; (3) investigating how the DNA repair machinery acts differently at DSBs versus at telomeres. We are currently investigating the mechanisms by which the MRN complex and the ATM kinase prevent telomere fusion.
This page was last updated on 2/22/2013.