RERF Report No. 5-13

Paper published in Genes and Environment §“Progerin, the protein responsible for the Hutchinson-Gilford Progeria Syndrome,
increases the unrepaired DNA damages following exposure to ionizing radiation”
Asao Noda, Shuji Mishima, Yuko Hirai, Kanya Hamasaki, Reid D. Landes, Hiroshi Mitani, KeiHaga, Tohru Kiyono, Nori Nakamura, Yoshiaki Kodama
Genes and Environment 2015 (October); 37(13):1-12(doi: 10.1186/s41021-015-0018-4)
Study Findings
We conducted a model-based investigation to test the hypothesis that genomic damageinduced by radiation contributes to abnormal cell nuclear morphology and premature aging. We
identified advanced nuclear envelope abnormalities and the expression of markers of prematureaging in cells with unrepaired DNA double strand breaks (DSBs) induced by radiation exposure.
We also found increased numbers of unrepaired DSBs in cells from patients with progeria, agenetic disease associated with rapid aging. Such cells express progerin, a mutant form of lamin
A protein responsible for progeria in humans, and feature abnormal nuclear envelope structure.
We concluded that nuclear lamin A, a protein thought to cause age-associated changes innuclear envelope structure, is related to the formation of radiation-induced unrepaired DSBs.
Explanation
We attempted to measure unrepaired DSBs as a new biomarker for detecting tissues
previously exposed to radiation and for estimating the radiation doses to which such tissues
were exposed. In our research, we noticed that cells with unrepaired DSBs developed abnormal
nuclear envelope morphology, with signs of premature aging. This led us to investigate whether
nuclear lamin A could be involved in DSB repair. Hutchinson-Gilford progeria syndrome(HGPS) is an extreme example of aging caused by abnormal nuclear envelope structure. Cellsof HGPS patients express progerin and have a nuclear envelope that is stiffer and more fragile
than normal.
1. Objectives
The objectives were to evaluate whether nuclear lamin A, a structural protein in themeshwork of the nuclear envelope, is involved in repairing radiation-induced DSBs and whether
the protein acts as a site for repairing or anchoring DSBs that are particularly resistant to repair.
2. Methods
Radiation-induced unrepaired DSBs and structural changes in the nuclear envelope weremeasured in cells from healthy humans and HGPS patients. Effects of farnesyl transferase

RERF Report No. 5-13

inhibitor (FTI), a new class of cancer drug, were also measured, because FTI suppresses thechanges in nuclear envelope structure caused by progerin. Finally, unrepaired DSBs and nuclear
envelope changes were assessed following telomerase gene induction, as telomerase geneinduction has been implicated in rejuvenating cells and making cells immortal.
3. Results(1) About 1% of radiation-induced DSBs persist in the cell nucleus as unrepaired DSBs (Nodaet al., J Cell Science 125:5280, 2012). Unrepaired DSBs inhibit cell division, indefinitely
arresting growth and causing premature aging. The numbers of unrepaired DSBs induced byradiation were at least two-fold higher in HGPS cells than in healthy cells. The numbers wereeven higher in cells with abnormal nuclear envelope structure.
(2) FTI treatment suppressed the anchoring of progerin to the nuclear membrane, therebyimproving the nuclear structure in HGPS cells. The number of unrepaired DSBs consequentlydecreased. Nuclear structure improved and unrepaired DSBs decreased in HGPS cells with cell
division capability restored by telomerase induction. The forced expression of telomerase
suppressed progerin expression and induced the expression of nuclear lamin B1, a cousin oflamin A. This expression profile is characteristic of young and undifferentiated cells.
(3) Structural changes in the nuclear envelope and the numbers of unrepaired DSBs were also
found to be correlated with radiation-induced premature aging in normal cells.
Study SignificancePrevious studies indicated that cells bearing unrepaired DSBs underwent prematuresenescence, even though this finding was not directly linked to physiological changes in humans.
In this study we show that the occurrence and anchoring of unrepaired DSBs caused byradiation exposure depend on nuclear envelope structure.

The Radiation Effects Research Foundation has studied A-bomb survivors and their offspring in
Hiroshima and Nagasaki for more than 60 years. RERF’s research achievements are considered theprincipal scientific basis for radiation risk assessment by the United Nations Scientific Committee on theEffects of Atomic Radiation (UNSCEAR) and for recommendations regarding radiation protection
standards by the International Commission on Radiological Protection (ICRP). RERF expresses its
profound gratitude to the A-bomb survivors and survivors’ offspring for their cooperation in our studies.

§Genes and Environment§, the official English-language journal of the Japanese Environmental Mutagen

Society, is published to facilitate communication among scientists around the world working in the fieldof genes and the environment. Articles are open access and published online.