The Karlseder Lab focuses on understanding the functions of mammalian telomeres. Telomeres, the protein-DNA complexes at the ends of linear chromosomes, are crucial in DNA replication, tumor suppression, and aging. Every time a primary human cell divides its telomeres get shorter, until critically short telomeres lead to terminal cell cycle arrest. We believe that a better understanding of this telomere shortening process will lead to an ability to influence the aging process, and as a result to the restriction of cancer cell growth. Currently, we work on several aspects of telomere structure and function:
- Interactions between the DNA damage machinery and telomeres
- Telomere processing during the cell cycle
- Changes in telomere length and chromatin structure
- G-rich and C-rich telomeric overhangs at chromosome ends
For more detailed information, check out a few recent Salk Press Releases about news and publications from the Karlseder Lab:
- A new ending to an old "tail" (April 21, 2011)
- Ticking of a cellular clock promotes seismic changes in the chromatin landscape associated with aging (October 3, 2010)
- How worms protect their chromosomes: Thereby hangs a surprising tail (March 11, 2008)
Previous Research
Our lab's research of telomere dynamics led to the finding that functional telomeres are recognized as double stranded breaks in G2 of the cell cycle. During a brief period after DNA replication telomeres recruit the DNA damage machinery, suggesting that this machinery is required for telomere processing. Further detailed analysis of telomeres during the cycle revealed that telomere processing occurs in two phases. In Phase 1 telomeres are replicated, and an ATR dependent DNA damage response monitors potential fork stalling and triggers repair synthesis and replication restart, when necessary. Then, after complete replication of telomeres, an ATM dependent damage response leads to recruitment of the homologous recombination machinery, which is required for formation of a protective structure at the end of chromosome. These results demonstrate that telomeres are processed similarly to double stranded breaks, and the cellular DNA repair machinery is involved in formation of functional chromosome ends.
We are also exploring telomere dynamics and telomerase function in the nematode C. elegans. Our lab has demonstrated that chromosome termini possess 3′ G-strand overhangs as well as 5′ C-strand overhangs.
C tails are as abundant as G tails and are generated by a well-regulated process. These two classes of overhangs are bound by two single-stranded DNA binding proteins, CeOB1 and CeOB2, which exhibit specificity for G-rich or C-rich telomeric DNA. Both CeOB1 and CeOB2 contain OB (oligo-saccharide/oligo-nucleotide binding) folds, which exhibit structural similarity to the second and first OB folds of the mammalian telomere binding protein hPOT1, respectively. Our results suggest that C. elegans telomere homeostasis relies on a novel mechanism that involves 5′ and 3′ single-stranded termini.
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