We will explore connections between telomere biology and disease in the Werner premature aging syndrome, using yeast and cultured human cells as model systems. Telomere shortening accompanies but plays an uncertain causal role in human aging. In contrast, it is clear that prevention of telomere shortening is required for the growth of most cancers. Werner syndrome is characterized by premature features of aging and by elevated rates of cancer, and is caused by loss of the RecQ-family helicase/exonuclease WRN. Evidence is accumulating that Werner cells have telomere defects, which might contribute to the premature aging and elevated cancer incidence, and WRN (and other RecQ helicases) may function in the repair of shortened telomeres. We will dissect the established role of the yeast RecQ homologue, Sgslp, in telomere maintenance. We will map the domains of Sgslp that, in yeast cells lacking telomerase, are required to prevent rapid senescence and telomere shortening, as well as defects in survivors of senescence. We will test alternative mechanisms to explain these defects, including defects in recombination or the formation of G-DNA structures at telomeres. We will also screen for other genetic factors that cooperate with Sgslp in telomere maintenance, including the generation of recombination dependent survivors of senescence. The role in human cells of the mechanisms revealed by studies in yeast, particularly those involving homologous recombination, will be tested by performing experiments in senescing human cultured cells, including those with mutations in WRN. These studies should illuminate the function of WRN at human telomeres and improve understanding of the role of telomeres in natural human aging and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG021521-03
Application #
7054775
Study Section
Special Emphasis Panel (ZRG1-CMAD (01))
Program Officer
Sierra, Felipe
Project Start
2004-05-01
Project End
2009-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
3
Fiscal Year
2006
Total Cost
$241,449
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Guha, Manti; Srinivasan, Satish; Guja, Kip et al. (2016) HnRNPA2 is a novel histone acetyltransferase that mediates mitochondrial stress-induced nuclear gene expression. Cell Discov 2:16045
Johnson, Jay E; Johnson, F Brad (2014) Methionine restriction activates the retrograde response and confers both stress tolerance and lifespan extension to yeast, mouse and human cells. PLoS One 9:e97729
Dong, Dawei W; Pereira, Filipe; Barrett, Steven P et al. (2014) Association of G-quadruplex forming sequences with human mtDNA deletion breakpoints. BMC Genomics 15:677
Platt, Jesse M; Ryvkin, Paul; Wanat, Jennifer J et al. (2013) Rap1 relocalization contributes to the chromatin-mediated gene expression profile and pace of cell senescence. Genes Dev 27:1406-20
Singh, Lakshman; Brennan, Tracy A; Kim, Jung-Hoon et al. (2013) Long-term functional engraftment of mesenchymal progenitor cells in a mouse model of accelerated aging. Stem Cells 31:607-11
Mason, Mark; Wanat, Jennifer J; Harper, Sandy et al. (2013) Cdc13 OB2 dimerization required for productive Stn1 binding and efficient telomere maintenance. Structure 21:109-120
Glineburg, M Rebecca; Chavez, Alejandro; Agrawal, Vishesh et al. (2013) Resolution by unassisted Top3 points to template switch recombination intermediates during DNA replication. J Biol Chem 288:33193-204
Wanat, Jennifer J; Johnson, F Brad (2012) Telomere stability and carcinogenesis: an off-again, on-again relationship. J Clin Invest 122:1962-5
Wang, Haitao; Chen, Qijun; Lee, Seoung-Hoon et al. (2012) Impairment of osteoblast differentiation due to proliferation-independent telomere dysfunction in mouse models of accelerated aging. Aging Cell 11:704-13
Yatsunyk, Liliya A; Bryan, Tracy M; Johnson, F Brad (2012) G-ruption: the third international meeting on G-quadruplex and G-assembly. Biochimie 94:2475-83

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