Abstract
IntroductionProgerin, 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.ResultsWe 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.ConclusionWe suggest that lamin A- or progerin-associated nuclear envelope is involved in cellular aging associated with DNA damage repair.Electronic supplementary materialThe online version of this article (doi:10.1186/s41021-015-0018-4) contains supplementary material, which is available to authorized users.
Highlights
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
Dysmorphic nuclei are commonly observed in HGPS cells starting from early passages of in vitro culture (Additional file 2: Figure S2), which is considered to be due to accumulation of progerin [26, 27]
We found that about 15 % of HGPS cells were already dysmorphic (ESR ratio ≥1.05) at population doublings 20 (PDs20), which corresponds to the middle period of in vitro HGPS cell aging (Fig. 1d)
Summary
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. Radiation-induced γH2AX foci are reported to persist in pig skin [2], mouse skin [3] and mouse pancreas [1] following exposure to high doses of radiation This suggests that the majority of cells in tissues with very slow turnover rate may accumulate unrepaired DSBs that occur either spontaneously or following exposure to radiation; e.g., mouse pancreatic cells replicate once in about 500 days and brain or kidney cells grow even more slowly [4, 5]. HGPS cells induced immortalization, with accompanying changes such as smoother nuclear shape and decreased number of 53BP1 foci, under steady-state conditions This could be due to the fact that cells bearing unrepairable DSBs were incapable of undergoing cell division following telomerase expression, and were excluded from the culture during the immortalization process (positive selection of relatively young cells).
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