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.
Hasty P, Livi CB, Dodds SG, Jones D, Strong R, Javors M, Fischer KE, Sloane L, Murthy K, Hubbard G, Sun L, Hurez V, Curiel TJ, Sharp ZD. eRapa restores a normal life span in a FAP mouse model. Cancer Prev Res (Phila). 2014 Jan;7(1):169-78.
Hu L, Kim TM, Son MY, Kim SA, Holland CL, Tateishi S, Kim DH, Yew PR, Montagna C, Dumitrache LC, Hasty P. Two replication fork maintenance pathways fuse inverted repeats to rearrange chromosomes. Nature. 2013 Sep 26;501(7468):569-72.
Hasty P, Sharp ZD, Curiel TJ, Campisi J. mTORC1 and p53: clash of the gods? Cell Cycle. 2013 Jan 1;12(1):20-5.
Livi CB, Hardman RL, Christy BA, Dodds SG, Jones D, Williams C, Strong R, Bokov A, Javors MA, Ikeno Y, Hubbard G, Hasty P, Sharp ZD. Rapamycin extends life span of Rb1+/- mice by inhibiting neuroendocrine tumors. Aging (Albany NY). 2013 Feb;5(2):100-10.
Kim TM, Rebel VI, Hasty P. Defining a genotoxic profile with mouse embryonic stem cells. Exp Biol Med (Maywood). 2013 Mar;238(3):285-93.