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Department of Molecular Medicine
 

Hasty E. Paul  Hasty,  D.V.M.

Professor

Profile and Contact Information | Research | Laboratory

RESEARCH

 

Research Program

We focus on the impact chromatin metabolism has on cancer and aging in genetically altered cells mice using embryonic stem cell/gene targeting technology. Specifically we study proteins important for the repair of DNA double - strand breaks by two different pathways. The first pathway is called recombinational repair by virtue that it utilizes a homologous template usually provided by the sister chromatid. To disrupt recombinational repair, we mutated Rad51 and found it to be essential for cellular proliferation and repair of DNA damaged by ionizing radiation. rad51 - mutant embryos die shortly after implantation. Next we determined that a cell cycle response contributed to embryonic lethality by crossing the rad51 - mutant mice to p53 - mutant mice. p53 is a tumor suppressor that is essential for stopping cellular proliferation after DNA damage. We also discovered that Rad51 functions by binding to a breast cancer susceptibility gene called Brca2 and mice with a subtle brca2 mutation exhibit a shortened life span due to increased cancer incidence. Thus, we established that the Rad51 pathway is important for suppressing tumors. The second pathway is called nonhomologus end joining (NHEJ) because it joins chromosomal ends without the use of a homologous template. To disrupt NHEJ, we mutated Ku80 (a.k.a. Ku86) and found that ku80 - mutant mice are relatively normal at birth; however, exhibit an early onset of characteristics associated with aging that include osteopenia, skin and follicular atrophy, liver degeneration and shortened life span. Early onset of sepsis and cancer shortened life span. In addition, cells derived from ku80 - mutant mice undergo premature cellular senescence that is dependent on the tumor suppressor protein p53. Ongoing research focuses on the molecular mechanisms important for both DNA repair pathways with special attention to aging and oncogenesis.

 

Selected Publications

  1. Hasty, P., Campisi, J., Hoeijmakers, J., van Steeg, H., Vijg, J. (2003) Aging and Genome Maintenance: Lessons from the mouse? Science. 299:1355-9.

  2. Hasty, P., and Vijg, J. (2004) Accelerating Aging by Mouse Reverse Genetics: A Rational Approach to Understand Longevity.Aging Cell. 3:55-65.

  3. Hasty, P., and Vijg, J. (2004) Rebuttal to Miller: 'Accelerated aging': a primrose path to insight?' Aging Cell. 3:67-9.

  4. Marple, T., Li, H., Hasty, P. (2004) A Genotoxic Screen: Rapid Analysis of Cellular Dose-Rsponse to a Wide-Range of Agents that either Damage DNA or Alter Genome Maintenance Pathways. Mut. Res. 554-253-766.

  5. Hasty, P. (2005) The Impact of DNA Damage, Genetic Mutation and Cellular Responses on Cancer Prevention, Longevity and Aging: Observations in Humans and Mice. Mech. Ageing Dev. Jan; 126(1):71-7.

  6. Ohbayashi, F., Balamotis, M.A., Kishimoto, A., Aizawa, E., Diaz, A., Hasty, P., Graham, F.L., Caskey, C.T., and Mitani, K. (2005) Correction of chromosomal mutation and random integration in embryonic stem cells with helper-dependent adenoviral vectors. Proc Natl Acad Sci. 102(38):13628-33.

  7. Yaneva, M., Li, H., Marple, T., and Hasty, P. (2005) Non-homologous end joining, but not homologous recombination, enables survival for cells exposed to a histone deacetylase inhibitor. Nucleic Acids Res. 33(16):5320-30.

  8. Hasty, P. and Vijg, J. (2005) Aging and p53: getting it straight. A commentary on a recent paper by Gentry and Venkatachalam. Aging Cell 4:331-3.

  9. Marple, T., Kim, T.-M., and Hasty, P. (2006) Embryonic Stem Cells Deficient for Brca2 or Blm Exhibit Divergent Gentoxic Profiles that Support Opposing Activities during Homologous Recombination. Mutat. Res. 602(1-2):110-20.

  10. Holcomb, V.B., Vogel, H., Marple, T., Kornegay, R.W. and Hasty, P. (2006) Ku80 and p53 suppress medulloblastoma that arise independent of Rag-1-Induced DSBs. Oncogene 25(54):7159-65.

  11. Van de Ven, M., Andressoo, J.-O., Holcomb, V.B., von Lindern, M, Jong, W.M., Zeeuw, C.I., Suh, Y. Hasty, P., Hoeijmakers, J.H., van der Horst, G.T., and Mitchell, J.R. (2006) Adaptive Stress Response in Segmental Progeria Resembles Long-Lived Dwarfism and Calorie Restriction in Mice. PloS Genet. 2(12):e192 [Epub ahead of print].

  12. Holcomb, V.B., Kim T.-M., Dumitrache, L., Ma, S., Chen, M. and Hasty, P. (2007) HPRT Minigene Generates Chimeric Transcripts as a by-product of gene targeting. Genesis 45(5): 275-81.

  13. Chen, M.J., Ma, S.M., Dumitrache, L.C., and Hasty, P. (2007) Biochemical And Cellular Characteristics Of The 3'->5' Exonuclease TREX2. Nucleic Acids Res. 35(8):2682-94.

  14. Van de Ven, M., Andressoo, J.-O., Holcomb, V.B., Hasty, P., Suh, Y., van Steeg, H., Garinis, G.A., Hoeijmakers, J.H., and Mitchell, J.R. (2007) Extended longevity mechanisms in short-lived progeroid mice: identification of a preservative stress response associated with successful aging. Mech Ageing Dev. 128(1):58-63.

  15. Holcomb, V. B., Vogel, H., and Hasty, P. (2007) Deletion of Ku80 Causes Early Aging Independent of Rag-1-Induced DSBs and SCID. Mech Ageing Dev.(In Press).

  16. Chen, M. J., Dumitrache, L. C., Wangsa, D., Ma, S. M., Padilla-Nash, H., Ried, T., and Hasty, P. (2007) Cisplatin depletes TREX2 and causes Robertsonian translocations as seen in TREX2 knockout cells. Cancer Res. (In Press).

  17. Gurley, K. E., Moser, R., Gu, Y., Hasty, P., and Kemp, C. J. Disabling DNA-PK sensitizes p53 null cells to DNA damage-induced apoptosis. (submitted).

  18. Li., H., Vogel, H., Holcomb, V. B., Gu, Y., and Hasty, P. (2007) Deletion of either Ku70, Ku80 or both causes early aging without increased cancer. Molec. Cell. Biol. (In Press).

  19. Li., H., Zhange, Y., Marple, T., Sobol, R. W, Lee, S. E., and Hasty, P. Ku80-deletion impairs base excision repair (submitted).

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