title: Progerin, the protein responsible for the Hutchinson-Gilford progeria syndrome, increases the unrepaired DNA damages following exposure to ionizing radiation.
abstract: BACKGROUND
  Progerin, the protein responsible for the Hutchinson-Gilford Progeria Syndrome (HGPS), is a partially deleted form of nuclear lamin A, and its expression has been suggested as a cause for dysfunctional nuclear membrane and premature senescence. To examine the role of nuclear envelop architecture in regulating cellular aging and DNA repair, we used ionizing radiation to increase the number of DNA double strand breaks (DSBs) in normal and HGPS cells, and analyzed possible relationship between unrepaired DSBs and cellular aging.
  
  
  RESULTS
  We found that HGPS cells are normal in repairing a major fraction of radiation-induced double strand breaks (M-DSBs)but abnormal to show increased amount of residual unrepaired DSBs (R-DSBs). Such unrepaired DSBs were 2.6 times (CI 95 %: 2.2-3.2) higher than that in normal cells one week after the irradiation, and 1.6 times (CI 95 %: 1.3-1.9) higher even one month after the irradiation. These damages tend to increase as the nuclear envelope become abnormal, a characteristic of both HGPS and normal human cells which undergo replicative senescence. The artificial, enforced over-expression of progerin further impaired the repair of M-DSBs, implying lamin A-associated nuclear membrane has an important role for DNA DSB repair. Introduction of telomerase gene function in HGPS cells reversed such aging phenotypes along with upregulation of lamin B1 and downregulation of progerin, which is a hallmark of young cells.
  
  
  CONCLUSIONS
  We suggest that lamin A- or progerin-associated nuclear envelope is involved in cellular aging associated with DNA damage repair.
authors.affiliation: Department of Genetics, Radiation Effects Research Foundation, 5-2 Hijiyama-Park, Minami-Ku, Hiroshima 732-0815 Japan.
authors.forename: Asao
authors.initials: A
authors.lastname: Noda
authors.affiliation: Department of Genetics, Radiation Effects Research Foundation, 5-2 Hijiyama-Park, Minami-Ku, Hiroshima 732-0815 Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Mishima
authors.affiliation: Department of Genetics, Radiation Effects Research Foundation, 5-2 Hijiyama-Park, Minami-Ku, Hiroshima 732-0815 Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Hirai
authors.affiliation: Department of Genetics, Radiation Effects Research Foundation, 5-2 Hijiyama-Park, Minami-Ku, Hiroshima 732-0815 Japan.
authors.forename: Kanya
authors.initials: K
authors.lastname: Hamasaki
authors.affiliation: Department of Statistics, Radiation Effects Research Foundation, 5-2 Hijiyama-Park, Minami-Ku, Hiroshima 732-0815 Japan.
authors.forename: Reid D
authors.initials: RD
authors.lastname: Landes
authors.affiliation: Department of Integrated Biosciences, Graduate School of Sciences, The University of Tokyo, Kashiwa-no-ha 5-1-5, Kashiwa, Chiba 277-8572 Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mitani
authors.affiliation: Division of Virology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Haga
authors.affiliation: Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Kiyono
authors.affiliation: Department of Genetics, Radiation Effects Research Foundation, 5-2 Hijiyama-Park, Minami-Ku, Hiroshima 732-0815 Japan.
authors.forename: Nori
authors.initials: N
authors.lastname: Nakamura
authors.affiliation: Department of Genetics, Radiation Effects Research Foundation, 5-2 Hijiyama-Park, Minami-Ku, Hiroshima 732-0815 Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kodama
keywords: Cell aging; FTI; HGPS; Radiation; Unrepairable DSB