Project 1

Genes affecting metabolism and longevity in C.elegans

Robert J. Shmookler Reis, DPhil
Professor

Departments of Geriatrics, Medicine, Biochemistry/Molecular Biology, and Pharmacology/Toxicology

B.A., Harvard University, Cambridge, MA

D.Phil., University of Sussex, Brighton, England, U.K.

Postdoctoral Training: University of California at San Diego; Mammalian Genome Unit, Edinburgh UK; McMaster University, Hamilton, Ontario, Canada

Research interests:

Molecular genetics of aging, cancer and osteoporosis

Elevated recombination predisposes cells to cancer initiation and progression. We were the first to note markedly increased levels of homologous recombination, and of expression for Rad51 recombinase, in all cancer cells and other immortal cell lines relative to normal diploid cells.  Homologous recombination is elevated in cells transformed by several oncogenes, and in normal cells exposed to known carcinogens (concordance = 1.0).  Cancer cells, either cultured in vitro or primary cells from patients, show markedly elevated recombination, expression of recombination-complex genes, loss of heterozygosity, and acquisition of drug resistance, relative to normal control cells – and all appear to be mediated by homologous recombination. We are working to develop these findings into new diagnostic, prognostic, and therapeutic approaches.

Genes governing bone density in mice and humans. Genetic loci causing natural variation in bone density were mapped using mouse interstrain crosses. By scanning the genome for linkage to genetic variation in bone density, 5  chromosome regions were identified with significant effects on spinal bone density at maturity, and two impact post-maturity change in bone density. Backcrossed lines of mice, retaining a short segment of "donor" strain genome in a "recipient" strain's genetic background, are then tested for affected bone traits.  A human region, corresponding to a mouse "post-maturity change" locus, is significantly and reproducibly associated with spinal (but not hip) BMD in a population of 3500 post-menopausal women.  The association peaks in the pir gene.

Metabolic indices of longevity.  We are working under an NIH program project grant to identify common metabolic profiles, including markers of oxidative damage and antioxidant defenses, that predict future longevity in young adults of four taxa (yeast, nematodes, insects, and mice).  In each model system, we are comparing normal-life-span controls to groups with extended life span due to genetic or dietary alteration.

Genes regulating longevity in the nematode, C. elegans.  We identified a dozen loci with very marked and significant effects on life span, comprising one-third of all such genes with similar effect.  Four loci have been isolated in a contrasting, uniform genetic background, and the donor regions have been narrowed and fine-mapped.  These loci cause natural variation in life span and specific stress resistances, differing among the four regions.  

Selected Publications
Peer-reviewed Publications (selected from >146 total):

1. Shmookler Reis RJ, Buss J, Green MH: Properties of the polyoma virus transcription complex obtained from mouse nuclei. Virology 57: 122-127, 1974.

2. Shmookler Reis RJ: Enzyme fidelity and metazoan aging. Interdisc. Topics Gerontol. 10: 11-23, 1976.

3. Shmookler Reis RJ, Biro PA: Sequence and evolution of mouse satellite DNA. J. Mol. Biol. 121: 357-374, 1978.

4. Shmookler Reis RJ, Goldstein S: Loss of reiterated DNA sequences during serial passage of human diploid fibroblasts. Cell 21:739-749, 1980.

5. Shmookler Reis RJ, Timmis JN, Ingle J: Divergence, differential methylation and interspersion of melon satellite DNA sequences. Biochem. J. 195:723-734, 1981.

6. Shmookler Reis RJ, Goldstein S: Interclonal variation in methylation patterns for expressed and non-expressed genes. Nucl. Acids Res. 10: 4293-4304, 1982.

7. Shmookler Reis RJ, Goldstein S: Mitochondrial DNA in mortal and immortal human cells: Genome number, integrity and methylation. J. Biol. Chem. 258:9078-9085, 1983.

8. Riabowol KT, Shmookler Reis RJ, Goldstein S: Interspersed repetitive and tandemly repetitive sequences are differentially represented in extrachromosomal covalently closed circular DNA of human diploid fibroblasts. Nucl. Acids Res. 13:5563-5584, 1985.

9. Shmookler Reis RJ, Srivastava A, Beranek D, Goldstein S: The human alphoid family of tandemly-repeated DNA: Sequence of cloned tetrameric fragments and analysis of familial divergence. J. Mol. Biol. 186:31-41, 1985.

10. Finn GK, Kurz BW, Cheng RZ, Shmookler Reis RJ: Homologous plasmid recombination is elevated in immortally transformed cells. Mol. Cell. Biol. 9: 4009-4017, 1989.

11. Shmookler Reis RJ, Finn GK, Smith K, Goldstein S: Clonal variation in gene methylation: c-H-ras and alpha-hCG regions vary independently in human fibroblast lineages. Mutation Res. 237: 45-57, 1990.

12. Thweatt R, Goldstein S, Shmookler Reis RJ: A universal primer mixture for sequence determination at the 3' ends of cDNAs. Anal. Biochem. 190: 314-316, 1990.

13. Cheng RZ, Murano S, Kurz BW, Shmookler Reis RJ: Homologous recombination is elevated in some Werner-like syndromes but not during normal in vitro or in vivo senescence of mammalian cells. Mutation Res. 237:259-269, 1991.

14. Murano S, Thweatt R, Shmookler Reis RJ, Jones RA, Moerman EJ, Goldstein S: Diverse gene sequences are overexpressed in Werner syndrome fibroblasts undergoing premature replicative senescence. Mol. Cell. Biol. 11: 3905-3914, 1991.

15. Ebert RH II, Cherkasova VA, Dennis RA, Wu JH, Ruggles S, Eudy Perrin T, Shmookler Reis RJ: Longevity-determining genes in Caenorhabditis elegans: Chromosomal mapping of multiple noninteractive loci. Genetics 135:1003-1010, 1993.

16. Egilmez NK, Shmookler Reis RJ: Age-dependent somatic excision of transposable element Tc1 in Caenorhabditis elegans. Mutation Res. 316: 17-24, 1994.

17. Egilmez NK, Ebert RH, and Shmookler Reis RJ: Strain evolution in Caenorhabditis elegans: Transposable elements as markers of interstrain evolutionary history. J. Molec. Evol. 40:372-381, 1995.

18. Ebert RH II, Shammas MA, Sohal BH, Sohal RS, Egilmez NK, Ruggles S, Shmookler Reis RJ: Defining genes that govern longevity in Caenorhabditis elegans.  Devel. Genet. 18:131 -143, 1996.

19. Xia SJ, Shammas MA, Shmookler Reis RJ: Reduced telomere length in ataxia-telangiectasia fibroblasts. Mutation Res. 364: 1-11, 1996.

20. Cheng RZ, Shammas MA, Li J, and Shmookler Reis RJ: Expression of SV40 large T antigen stimulates reversion of a chromosomal gene duplication in human cells. Exper. Cell Res. 234: 300-312, 1997.

21. Shammas MA, Xia SJ, Shmookler Reis RJ: Induction of duplication reversion, by wild-type and mutated SV40 T antigen, covaries with ability to induce host DNA synthesis. Genetics 146:1417-28, 1997.

22. van Swinderen B, Ebert RH, Shook DR, Cherkasova VA, Johnson TE, Shmookler Reis RJ, Crowder CM: Quantitative trait loci controlling halothane sensitivity in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 94: 8232-8237, 1997.

23. Xia SJ, Shammas MA, Shmookler Reis RJ: Elevated recombination in immortal human cells is mediated by HsRAD51 recombinase. Mol. Cell. Biol. 17: 7151-7158, 1997.

24. Li J, Ayyadevara R, Shmookler Reis RJ: Carcinogens stimulate intrachromosomal homologous recombination at an endogenous locus in human diploid fibroblasts. Mutation Res. 385:173-193, 1998.

25. Shammas MA, Simmons C, Corey DR, Shmookler Reis RJ: Telomerase inhibition by peptide nucleic acids reverses "immortality" of transformed human cells. Oncogene 46: 6191-6200, 1999.

26. Beneš H, Shelton RS, Weinstein RS, Zheng W, Thaden JJ, Jilka RL, Manolagas SC, Shmookler Reis RJ: Chromosomal mapping of osteopenia-associated quantitative trait loci using closely related mouse strains. J. Bone Min. Res. 15:26-33, 2000.

27. Cherkasova VA, Ayyadevara S, Egilmez NK, Shmookler Reis RJ. Diverse Caenorhabditis elegans genes that are upregulated in dauer larva also show elevated transcript levels in long-lived, aged, or starved adults. J. Mol. Biol. 300: 433-448, 2000.

28. Ayyadevara S, Thaden JJ, Shmookler Reis RJ. Anchor Polymerase Chain Reaction Display: A high-throughput method to resolve, score and isolate dimorphic genetic markers based on interspersed repetitive DNA elements. Anal. Biochem. 284:19-28, 2000.  See also pp. 1–18, op cit., companion paper.

29. Ayyadevara S, Ayyadevara R, Hou S, Thaden JJ, Shmookler Reis RJ. Genetic mapping of quantitative trait loci governing longevity of Caenorhabditis elegans, in recombinant-inbred progeny of a Bergerac-BO × RC301 interstrain cross. Genetics 157: 655-666, 2001.

30. Miller RA, Galecki A, Shmookler Reis RJ. Interpretation, design, and analysis of gene array expression experiments. J. Geront. Biol. Sci. 56A: B52-B57, 2001. See also J. Geront. Biol. Sci. 56A: B327-330, 2001.

31. Ayyadevara S, Ayyadevara R, Vertino A, Galecki A, Thaden JJ, Shmookler Reis RJ. Genetic loci affecting fitness and life span in Caenorhabditis elegans: Categorical trait interval mapping in CL2a × Bergerac-BO recombinant-inbred worms. Genetics 163:557-570, 2003.

32. Shammas MA, Shmookler Reis RJ, Cheng L, Koley H, Hurley LH, Anderson KC, Munshi NC.  Telomerase inhibition and cell growth arrest after telomestatin treatment in multiple myeloma. Clin. Cancer Res.10:770–776, 2004.

33. Shammas MA, Liu X-H, Gavory G, Raney KD, Balasubramanian S, and Shmookler Reis RJ, Targeting the single-strand G overhang of telomeres with PNA inhibits cell growth and induces apoptosis of human immortal cells.  Exper. Cell Res. 295: 204–214, 2004.

34. Shammas MA, Shmookler Reis RJ, Cheng L, Koley H, Hurley LH, Anderson KC, Munshi NC.  Telomerase inhibition and cell growth arrest after telomestatin treatment in multiple myeloma. Clin Cancer Res10:770–776, 2004.

35. Khaidakov M, Chavannes-Turesky N, Cooney CA, Dupont-Versteegden EE, Kennedy RH, Siegel ER, Khaidakova G, Shmookler Reis RJ.  Contribution of de novo point mutations to the overall mutational burden in mitochondrial DNA of adult rats. Exper Gerontol 40:396-402, 2005.

36. Ayyadevara S, Engle MR, Singh SP, Dandapat A, Lichti CF, Beneš H, Liebau E, Shmookler Reis RJ, and Zimniak P.  Life span and stress resistance of Caenorhabditis elegans are increased by expression of glutathione transferases capable of metabolizing the lipid peroxidation product 4-hydroxynonenal.  Aging Cell, in press 2005.

37. Ayyadevara S, Dandapat A, Singh SP, Beneš H, Zimniak L, Shmookler Reis RJ and Zimniak P.  Life span extension in hypomorphic daf-2 mutants of C. elegans is partially mediated by glutathione transferase CeGSTP2-2.  Aging Cell, in press 2005.

38. Khaidakov M, Shmookler Reis RJ.  Possibility of selection against mtDNA mutations in tumors. (2005). Molecular Cancer, in press 2005.

39. Parsons CA, Mroczkowski HJ, McGuigan FEA, Albagha OME, Manolagas SC, Reid DM, Ralston SH, Shmookler Reis RJ. Interspecies synteny mapping identifies a quantitative trait locus for bone mineral density on human chromosome Xp22. Hum Molec Genet, in press 2005.

40. Shammas MA, Shmookler Reis RJ, Koley H, Li C, and Munshi NC.  Homologous recombination mediates DNA instability in myeloma.  Submitted 2005.

Recent Reviews and Chapters in Books/Proceedings (selected from a total of 20):

1. Shmookler Reis RJ and Shammas M: DNA instability, telomeric recombination, and cell transformation. In: The role of DNA damage and repair in cellular aging. (BA Gilchrest and VA Bohr, eds.), Elsevier, Amsterdam; 2001, pp. 135-151.

2. Shmookler Reis RJ: Theories of Aging, in Lipschitz DA, Shmookler Reis RJ, and Sullivan DH: The Biology of Aging. In: Cecil Essentials of Medicine, Fifth Edition (TE Andreoli, Editor-in-Chief), W.B. Saunders, Philadelphia; 2001, pp. 1001-1010.

3. Shmookler Reis, RJ: Toward a unified theory of aging -- What mammals can learn from worms and other ephemeral creatures. In: Oxidative Stress and Aging (RG Cutler and H. Rodriguez, eds.), World Scientific Publishing, Singapore; 2003, pp. 1263–1283.

4. Shmookler Reis RJ. From QTL mapping to genes: The long and winding road. J Bone Min Res18:186-189, 2003.

5. McEwen JE, Zimniak P, Mehta JL and Shmookler Reis, RJ.  Molecular pathology of aging and its implications for senescent coronary atherosclerosis.  Curr Opin Cardiol, 20:399-406 2005.

E-mail:   ReisRobertJS@uams.edu

Office:    (501) 257-5560     FAX:   (501) 257-5578

Mailing address:  VA Medical Center - Research 151

Room GB-105 (couriers only)

Little Rock, AR 72205