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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.
- Livi CB, Hardman RL, Christy BA, Dodds SG, Jones D, Williams C, Strong R, Bokov A, Javors MA, Ikeno Y, Hubbard G, Hasty P, and Sharp ZD: (2013) Rapamycin extends life span of Rb1+/- mice by inhibiting neuroendocrine tumors. AGING (Albany NY). 5(2): 100-10. ePublished www.impactaging.com.
- Kim TM, Ko JH, Hu L, Kim SA, Bishop AJ, Vijg J, Montagna C, and Hasty P: (2012) RAD51 mutants cause replication defects and chromosomal instability. Mol Cell Biol. 32(18): 3663-80.
- Dumitrache LC, Hu L, Son MY, Li H, Wesevich A, Scully R, Stark J, and Hasty P: (2011) Trex2 enables spontaneous sister chromatid exchanges without facilitating DNA double-strand break repair. Genetics. 188(4): 787-97.
- Kim TM, Ko JH, Choi YJ, Hu L, and Hasty P: (2011) The phenotype of FancB-mutant mouse embryonic stem cells. Mutat Res. 712(1-2): 20-7.
- Choi YJ, Son MY, and Hasty P: (2011) One-step knockin for inducible expression in mouse embryonic stem cells. Genesis. 49(2): 92-7.
- Roberts SA, Strande N, Burkhalter MD, Strom C, Havener JM, Hasty P, and Ramsden DA: (2010) Ku is a 5'-dRP/AP lyase that excises nucleotide damage near broken ends. Nature. 464(7292): 1214-7.
- Hasty P: (2010) Rapamycin: the cure for all that ails. J Mol Cell Biol. 2(1): 17-9.
- Bennardo N, Gunn A, Cheng A, Hasty P, and Stark JM: (2009) Limiting the persistence of a chromosome break diminishes its mutagenic potential. PLoS Genet. 5(10): e1000683.
- Holcomb VB, Vogel H, and Hasty P: (2009) Unlike p53, p27 failed to exhibit an anti-tumor genetic interaction with Ku80. Cell Cycle. 8(15): 2463-6.
- Li H, Choi YJ, Hanes MA, Marple T, Vogel H, and Hasty P: (2009) Deleting Ku70 is milder than deleting Ku80 in p53-mutant mice cells. Oncogene. 28(16): 1875-8.
- Dumitrache LC, Hu L, and Hasty P: (2009) TREX2 exonuclease defective cells exhibit double-strand breaks and chromosomal fragments but not Robertsonian translocations. Mutat Res. 662(1-2): 84-7.
- Gurley KE, Moser R, Gu Y, Hasty P, and Kemp CJ: (2009) DNA-PK suppresses a p53 independent apoptotic response to DNA damage. EMBO Rep. 10(1): 87-93.
- Li H, Vogel H, Holcomb VB, Gu Y, and Hasty P: (2007) Deletion of Ku70, Ku80, or both causes early aging without substantially increased cancer. Molec Cell Biol. 27(23): 8205-14.
- Chen MJ, Dumitrache LC, Wangsa D, Ma SM, Padilla-Nash H, Ried T, and Hasty P: (2007) Cisplatin depletes TREX2 and causes Robertsonian translocations as seen in TREX2 knockout cells. Cancer Res. 67(19): 9077-83.
- Holcomb VB, Vogel H, and Hasty P: (2007) Deletion of Ku80 causes early aging independent of chronic inflammation and Rag-1-induced DSBs. Mech Ageing Dev. 128(11-12): 601-8.
- Van de Ven M, Andressoo JO, Holcomb VB, Hasty P, Suh Y, van Steeg H, Garinis GA, Hoeijmakers JH, and Mitchell JR: (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.
- Chen MJ, Ma SM, Dumitrache LC, and Hasty P: (2007) Biochemical and cellular characteristics of the 3'->5' exonuclease TREX2. Nucleic Acids Res. 35(8): 2682-94.
- Holcomb VB, Kim TM, Dumitrache LC, Ma SM, Chen MJ, and Hasty P: (2007) HPRT minigene generates chimeric transcripts as a by-product of gene targeting. Genesis. 45(5): 275-81.
- Van de Ven M, Andressoo JO, Holcomb VB, von Lindern M, Jong WM, Zeeuw CI, Suh Y, Hasty P, Hoeijmakers JH, van der Horst GT, and Mitchell JR: (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].
- Holcomb VB, Vogel H, Marple T, Kornegay RW, and Hasty P: (2006) Ku80 and p53 suppress medulloblastoma that arise independent of Rag-1-Induced DSBs. Oncogene. 25(54): 7159-65.
- Marple T, Kim TM, and Hasty P: (2006) Embryonic stem cells deficient for Brca2 or Blm exhibit divergent genotoxic profiles that support opposing activities during homologous recombination. Mutat Res. 602(1-2): 110-20.
- 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(6): 331-3.
- 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.
- Ohbayashi F, Balamotis MA, Kishimoto A, Aizawa E, Diaz A, Hasty P, Graham FL, Caskey CT, and Mitani K: (2005) Correction of chromosomal mutation and random integration in embryonic stem cells with helper-dependent adenoviral vectors. Proc Natl Acad Sci USA. 102(38): 13628-33.
- 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. 126(1): 71-7.
- Marple T, Li H, and Hasty P: (2004) A genotoxic screen: rapid analysis of cellular dose-response to a wide range of agents that either damage DNA or alter genome maintenance pathways. Mutat Res. 554(1-2): 253-66.
- Hasty P and Vijg J: (2004) Rebuttal to Miller: 'Accelerated aging:' a primrose path to insight?' Aging Cell. 3(2): 67-9.
- Hasty P and Vijg J: (2004) Accelerating aging by mouse reverse genetics: a rational approach to understanding longevity. Aging Cell. 3(2): 55-65.
- Hasty P, Campisi J, Hoeijmakers J, van Steeg H, and Vijg J: (2003) Aging and genome maintenance: lessons from the mouse? Science. 299(5611): 1355-9.