Telomeres are the natural ends of linear chromosomes. In mammals they consist of the repeated sequence TTAGGG that can stretch for up to 150 kb in mice, and 15 kilobase pairs in humans. The very end of the telomeres is made up of a single stranded overhang of the G rich 3' strand that can be up to 300 nucleotides long. A number of proteins bind specifically to the telomeric repeats. The telomeric repeat binding factors TRF1 and TRF2 bind to the double stranded regions of the chromosome ends, and form complexes there with their interacting proteins. TRF1 interacting factors are Tin2, tankyrase 1 and 2 and Pot1, all of which have been implicated in telomere length regulation. TRF2 interacts with the MRN complex hRapl, and has been suggested to play a major role in telomere protection. Werner Syndrome is a segmental premature aging disorder, where patients show many signs of old age already with 30 to 40 years. Additionally patients have a high incidence of cancer, and Werner Syndrome cells frequently show genome instability. Blooms syndrome is caused by mutations in a helicase related to the Werner protein, and patients also suffer from premature aging and cancer. Our preliminary data suggest that Werner syndrome could be caused by a dysfunction in telomere replication, and for the first time links telomere dysfunction to these aging syndromes.
In AIM1 we will analyze telomere structure in Werner Syndrome cells, investigate the role of telomerase in telomere rescue and maintenance, and define the relationship between telomeres and DNA damage signals.
AIM2 focuses on the role of WRN and other RecQ helicases in replication of G rich structures, as well as the interaction of WRN with telomeric proteins.
In AIM 3 we plan to study the redundancy of WRN with other members of the RecQ helicase family on replication. Furthermore we will investigate the effects of RecQ helicase dependent telomere dysfunction on genome instability in these syndromes. Relevance: Werner Syndrome is a premature aging disease with a high frequency of cancer. Here we aim to investigate the role of telomere function in the syndrome, and to elucidate the connection between telomere replication, aging and cancer in Werner Syndrome. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG025837-01A2
Application #
7149493
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Sierra, Felipe
Project Start
2006-08-01
Project End
2011-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
1
Fiscal Year
2006
Total Cost
$314,060
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Rivera, Teresa; Haggblom, Candy; Cosconati, Sandro et al. (2017) A balance between elongation and trimming regulates telomere stability in stem cells. Nat Struct Mol Biol 24:30-39
Lackner, Daniel H; Raices, Marcela; Maruyama, Hugo et al. (2012) Organismal propagation in the absence of a functional telomerase pathway in Caenorhabditis elegans. EMBO J 31:2024-33
Hayashi, Makoto T; Cesare, Anthony J; Fitzpatrick, James A J et al. (2012) A telomere-dependent DNA damage checkpoint induced by prolonged mitotic arrest. Nat Struct Mol Biol 19:387-94
Barefield, Colleen; Karlseder, Jan (2012) The BLM helicase contributes to telomere maintenance through processing of late-replicating intermediate structures. Nucleic Acids Res 40:7358-67
Oganesian, Liana; Karlseder, Jan (2011) Mammalian 5' C-rich telomeric overhangs are a mark of recombination-dependent telomere maintenance. Mol Cell 42:224-36
Orazio, Nicole I; Naeger, Colleen M; Karlseder, Jan et al. (2011) The adenovirus E1b55K/E4orf6 complex induces degradation of the Bloom helicase during infection. J Virol 85:1887-92
Flynn, Rachel Litman; Centore, Richard C; O'Sullivan, Roderick J et al. (2011) TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA. Nature 471:532-6
Lackner, Daniel H; Durocher, Daniel; Karlseder, Jan (2011) A siRNA-based screen for genes involved in chromosome end protection. PLoS One 6:e21407
O'Sullivan, Roderick J; Kubicek, Stefan; Schreiber, Stuart L et al. (2010) Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeres. Nat Struct Mol Biol 17:1218-25
O'Sullivan, Roderick J; Karlseder, Jan (2010) Telomeres: protecting chromosomes against genome instability. Nat Rev Mol Cell Biol 11:171-81

Showing the most recent 10 out of 13 publications