Cell senescence and apoptosis are thought to contribute to age-related diseases in mammals, and can be induced by critically shortened and thus uncapped telomeres. In humans, telomere shortening accompanies aging, and there is increasing evidence that shortening impairs tissue homeostasis. While maintenance of telomeres by telomerase is well understood, the roles of other telomere maintenance pathways are less well defined. The human Werner progeroid syndrome, caused by deficiency of the WRN RecQ-family helicase, is characterized by defects in telomere maintenance. Several lines of investigation, including our own work with mouse WRN and the S. cerevisiae homolog Sgs1, indicate roles for RecQ helicases in telomere maintenance by homologous recombination (HR)-based and G-quadruplex (G4) DNA-based mechanisms. Here we will investigate novel aspects of telomere maintenance involving RecQ helicases, G4-DNA, and HR. These will be investigated in three specific aims: 1) Determine the mechanisms by which deletion of the histone acetyltransferase encoded by SAS2 extends, in an HR- dependent fashion, the lifespan of telomerase mutants, 2) Investigate how the absence of Sgs1 enables cells lacking telomerase and homologous recombination to form survivors of telomere loss, and 3) Test the hypothesis that RecQ helicases can modulate telomere maintenance mechanisms via regulation of G4-DNA formation.
These aims will be carried in S. cerevisiae, which provides an experimentally tractable model in which to dissect mechanisms, and findings from yeast will then be tested in mice and cultured murine and human cells. Mechanism will be explored through the use of established genetic, biochemical, pharmacological, molecular and cell biological approaches. Understanding how RecQ helicases, HR, G4-DNA, and histone acetyltransferases collaborate to regulate telomere maintenance will offer new insights into aging and cancer biology, and should provide new targets for the future development of therapeutics aimed at treating age- related diseases and malignancies.
Telomeres, the ends of chromosomes, play important roles in aging and the development of cancer. We are studying novel mechanisms by which telomeres are maintained, including 1) roles for the RecQ subtype of DNA helicase that, when absent, can lead to human premature aging and cancer diseases, 2) roles for homologous recombination and 3) roles for unusual DNA structures called G-quadruplexes. These studies will help illuminate mechanisms by which telomeres are maintained and will thus help identify new targets for treating diseases of aging, including cancer.
|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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