Interactions between the telomeres and DNA damage response machinery
Telomeres have an apparent paradoxical relationship with proteins that function in DNA damage response and repair. A major function of telomeres is to mask chromosome ends from being recognized as DNA breaks, however, telomeres also interact normally with a number of factors that play a role in the DNA damage response. Proteins and protein complexes, such as the MRN complex, the ATM and ATR kinases, 53BP1 and players in the chromatin ubiquitin pathway all localize to both protected and deprotected telomeres. Previous work from our lab has suggested the association of DNA damage response proteins with telomeres is necessary to establish the protective chromosome end structure after telomere replication. Our goal is to understand the function of telomere associated DNA damage response machinery in the context of protected and deprotected chromosome ends.
Cellular response to deprotected telomeres
Telomere structure fluctuates between protected and unprotected states during the cell cycle and as a consequence of replicative aging. We are investigating these changes in detail, focusing on how deprotected telomeres are propagated through phases of the cell cycle, how the DNA damage response signaling from deprotected telomeres varies during cell cycle phases, and how primary and cancer cells react to the presence of deprotected telomeres.
Telomere dependent prolonged mitotic arrest checkpoint
We recently demonstrated that prolonged mitotic arrest in human cells results in programmed telomere deprotection and upregulation of DNA damage response signaling and cell cycle arrest. This discovery demonstrated a novel mechanism of telomere deprotection. We are now working to understand the mitotic duration checkpoint in detail and to investigate the effect of mitotic telomere deprotection on genome stability and oncogenic transformation.
Telomere driven changes in global chromatin structure
Telomere length and protective capacity is altered as a consequence of replicative aging. We recently found that shortened telomeres in aging cells emit chronic damage signals, which impact histone synthesis and lead to genome wide chromatin alteration in aged cells. We propose this is the mechanism by which the localized damage signal at shortened telomeres influences chromatin structure throughout the nucleus. Our goal is to understand how telomere-driven changes in chromatin structure impact the aging program and the consequence this may have on gene expression in aged cells.
5' single-strand C-rich telomeric overhangs
Terminal single-strand 3'-overhangs of G-rich telomeric repeats are well characterized and are believed to provide a critical role in maintaining the protective structure at chromosome ends. Our laboratory discovered the existence of terminal 5'-overhangs of C-rich telomeric sequence at nematode telomeres and at the telomeres in mammalian cells that rely on the recombination-dependent Alternative Lengthening of Telomeres (ALT) pathway for telomere length maintenance. We proposed a model in nematodes where chromosome ends harboring a 5' C-rich overhang played a role in the regulation of telomeric recombination, and that C-rich overhangs in mammals can serve as both a template for, and outcome of, recombination events at telomeres. We are currently focusing on understanding how 5' C-rich overhangs are generated and their putative functions in mammals and nematodes.
Regulation of Alternative Lengthening of Telomeres (ALT)
A sizeable minority of human tumors (10 to 15%) maintains their telomere length by the telomerase-independent ALT pathway. We discovered that ALT activity is enriched in nematodes by suppressing the function of CeOB2, a protein that binds specifically to the 5’ C-rich overhang. Based on this observation, we generated the first multicellular organism that exclusively uses ALT to maintain telomere length. Our goal is to use this valuable tool to study the induction and maintenance of ALT and to establish the worm as a model system to study ALT in human cancer.
© 2016 Salk Institute for Biological Studies
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