Robert J. Shmookler-Reis, Ph.D.

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

D.Phil., University of Sussex, Brighton, England, U.K.
B.A., Harvard University, Cambridge, MA

Molecular genetics of aging

Genes governing bone density in mice and humans. Gene regions responsible for low bone density were mapped in mouse interstrain crosses. When a low-bone-density strain is crossed to either of two control strains, spinal density varies widely among F2 progeny. By scanning the genome for locations cosegregating with bone density, 5 highly-significant genetic regions were identified that govern mature spinal bone density in mice, and another two regions affect post-maturity change in bone density. Offspring of such crosses were mated to one parental strain, and progeny inheriting just the implicated region from the other strain are followed with strain-specific markers. The resulting lines of mice, after 8-11 generations, retain only a few percent of the "donor" strain genome, within the "recipient" strain's genetic background. A human region was identified with conserved synteny to a mouse "post-maturity change" locus, and found to be associated with spinal BMD in post-menopausal female subjects.          

Selected Publications
Peer-reviewed Publications (selected, from >136 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: A sensitive microassay of nucleic acids. Anal. Biochem. 10:821-823,1978.

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

6. Shmookler Reis RJ, Goldstein S: Mechanisms moleculaires du vieillissement cellulaire (Molecular mechanisms for cellular aging). Assoc. Canadienne Francaise pour l'Avancement des Sciences (ACFAS) Annales 7:143-157, 1981.

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

8. Harley CG, Shmookler Reis RJ, Goldstein S: Changes in repeated DNA array size in a cell population due to unequal recombination. J. Theoret. Biol. 94: 1-12, 1982.

9. Shmookler Reis RJ, Goldstein S: Variability of DNA methylation patterns during serial passage of human diploid fibroblasts. Proc. Natl. Acad. Sci. USA 79: 3949-3953, 1982.

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

11. 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. 12. Goldstein S, Shmookler Reis RJ: Genetic modifications during cellular aging. Mol. Cell. Biochem. 64: 15-30, 1984.

12. Srivastava A, Norris JS, Shmookler Reis RJ, Goldstein S: c-Ha-ras-1 proto- oncogene amplification and overexpression during the limited replicative life span of normal human fibroblasts. J. Biol. Chem. 260:6404-6409, 1985.

13. 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.

14. Goldstein S, Shmookler Reis RJ: Methylation patterns in the gene for the alpha subunit of chorionic gonadotropin are inherited with variable fidelity in clonal lineages of human fibroblasts. Nucl. Acids Res. 13:7055-7065, 1985.

15. 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.

16. Shmookler Reis RJ: Model systems for aging research: syncretic concepts and diversity of mechanisms. Genome 31:406-412, 1989.

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

18. 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.

19. 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.

20. Goldstein S, Jones RA, Hardin JW, Braunstein GD, and Shmookler Reis RJ: Expression of alpha and beta human chorionic gonadotropin subunits in cultured human cells. In Vitro Cell. Dev. Biol. 26: 857-864, 1990.

21. 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.

22. 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.

23. 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.

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

25. 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.

26. 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.

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

28. 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.

29. Shammas MA, Xia SJ, Shmookler Reis RJ: Induction of duplication reversion, by wild-type and mutated SV40 T antigen, covaries with the ability to induce host DNA synthesis. Genetics 146:1417-1428, 1997.

30. 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.

31. Nikitin AG, Shmookler Reis RJ: Role of transposable elements in age-related genomic instability. Genet. Research, Cambridge 69: 183-195, 1997.

32. 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.

33. 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.

34. Shammas MA, Shmookler Reis RJ: Recombination and its roles in DNA repair, cellular immortalization and cancer. AGE J. 22:71-88, 1999.

35. 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.

36. Thaden JJ, Shmookler Reis RJ: Ammonia, respiration, and longevity in nematodes. J. Amer. Aging Assoc. 23: 75-84, 2000.

37. 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.

38. 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.

39. 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.

40. Ayyadevara S, Thaden JJ, Shmookler Reis RJ. Discrimination of primer 3'-nucleotide mismatch by Taq DNA polymerase during polymerase chain reaction. Anal. Biochem. 284: 1-18, 2000.

41. 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.

42. Batchu RB, Shammas MA, Wang JY, Shmookler Reis RJ, Munshi NC: Expression of AAV Rep proteins in SV40-transformed and untransformed cells: Reciprocal interaction with host DNA synthesis. Intervirology. 44: 298-305, 2001.

43. Miller RA, Galecki A, Shmookler Reis RJ. Interpretation, design, and analysis of gene array expression experiments. J. Gerontol. Biol. Sci. 56A: B52-B57, 2001. See also J. Gerontol. Biol. Sci. 56A: B327-B330, 2001.

44. Batchu RB, Shammas MA, Shmookler Reis RJ, Munshi NC: Interaction of Adeno-Associated Virus Rep78 with SV40 T antigen: Implications for Rep protein expression leading to inhibition of SV40-induced cell proliferation. Intervirology 45:115-118, 2002.

45. 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.

46. Shmookler Reis RJ.  From QTL mapping to genes: The long and winding road. J. Bone Min. Res. 18:186-189, 2003.

Reviews and Chapters in Books/Proceedings (selected from a total of 17):

1. Shmookler Reis RJ, Moerman EJ, Goldstein S: DNA methylation, maintenance CpG methylase, and senescence. In: Growth Control During Cellular Aging (Warner HR, Wang E, eds). CRC Press, Boca Raton FL; 1989, pp. 191-202.

2. Shmookler Reis RJ: The molecular pathology of senescence. In: Review of Biological Research in Aging, Vol. 4 (M. Rothstein, ed.) A.R. Liss, New York NY; 1990, pp. 293-313.

3. 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.

4. 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.

5. 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; in press 2002.