It has been suggested that ReqQ-associated diseases may link genomic stability, cancer and aging. However, the functions of RecQ helicases are still unknown. Sgs1 (also known as top 3 slow growth suppressor) is the only RecQ helicase in S. cerevisiae. David Sinclair is a new investigator who has identified two separable functions for Sgs1 in telomere maintenance and has also shown that mouse WRN (another RecQ helicase) can substitute for Sgs1 function. The investigator has observed that telomerase negative yeast cells lacking Sgs1 senesce more rapidly (possess only 40 percent lifespan of wild type cells) due to accelerated telomere attrition. The mechanism involves movement of telomere proteins (SIRs) to the nucleolus causing rDNA instability and fragmentation. In addition, cells lacking Sgs1 are unable to recover efficiently from senescence, are completely defective in the type II ALT pathway, and rare survivors grow poorly. Lastly, another function of Sgs1 may involve telomere capping in cells that engage the ALT pathway. The focus of this proposal is to characterize the role of Sgs1 in telomere maintenance and to understand more about how alternative pathways to telomerase are regulated. The experiments proposed should provide insights into function of human RecQ helicases (mutations of which may be important in human diseases such as Werner's, Bloom's and Rothmund-Thomson syndromes) and how cancer cells may be able to proliferate in the absence of telomerase.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG019719-01
Application #
6364506
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Sierra, Felipe
Project Start
2001-09-30
Project End
2006-08-31
Budget Start
2001-09-30
Budget End
2002-08-31
Support Year
1
Fiscal Year
2001
Total Cost
$260,307
Indirect Cost
Name
Harvard University
Department
Pathology
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Rajman, Luis; Chwalek, Karolina; Sinclair, David A (2018) Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence. Cell Metab 27:529-547
Das, Abhirup; Huang, George X; Bonkowski, Michael S et al. (2018) Impairment of an Endothelial NAD+-H2S Signaling Network Is a Reversible Cause of Vascular Aging. Cell 173:74-89.e20
Schultz, Michael B; Lu, Yuancheng; Braidy, Nady et al. (2018) Assays for NAD+-Dependent Reactions and NAD+ Metabolites. Methods Mol Biol 1813:77-90
Costford, Sheila R; Brouwers, Bram; Hopf, Meghan E et al. (2018) Skeletal muscle overexpression of nicotinamide phosphoribosyl transferase in mice coupled with voluntary exercise augments exercise endurance. Mol Metab 7:1-11
Longchamp, Alban; Mirabella, Teodelinda; Arduini, Alessandro et al. (2018) Amino Acid Restriction Triggers Angiogenesis via GCN2/ATF4 Regulation of VEGF and H2S Production. Cell 173:117-129.e14
Dai, Han; Sinclair, David A; Ellis, James L et al. (2018) Sirtuin activators and inhibitors: Promises, achievements, and challenges. Pharmacol Ther 188:140-154
Mitchell, Sarah J; Bernier, Michel; Aon, Miguel A et al. (2018) Nicotinamide Improves Aspects of Healthspan, but Not Lifespan, in Mice. Cell Metab 27:667-676.e4
Uddin, Golam Mezbah; Youngson, Neil A; Doyle, Bronte M et al. (2017) Nicotinamide mononucleotide (NMN) supplementation ameliorates the impact of maternal obesity in mice: comparison with exercise. Sci Rep 7:15063
Pollack, Rena M; Barzilai, Nir; Anghel, Valentin et al. (2017) Resveratrol Improves Vascular Function and Mitochondrial Number but Not Glucose Metabolism in Older Adults. J Gerontol A Biol Sci Med Sci 72:1703-1709
Mohamad, Mashani; Mitchell, Sarah Jayne; Wu, Lindsay Edward et al. (2016) Ultrastructure of the liver microcirculation influences hepatic and systemic insulin activity and provides a mechanism for age-related insulin resistance. Aging Cell 15:706-15

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