title: An association between low-dose hyper-radiosensitivity and the early G2-phase checkpoint in normal fibroblasts of cancer patients.
abstract: In our previous study, low-dose hyper-radiosensitivity (HRS) effect was demonstrated for normal fibroblasts (asynchronous and G2-phase enriched) of 4 of the 25 cancer patients investigated. For the rest of patients, HRS was not defined in either of the 2 fibroblast populations. Thus, the study indicated that G2-phase enrichment had no influence on HRS identification. The conclusion contradicts that reported for human tumor cells, and suggests different mechanism of HRS in normal human cells. In the present paper we report, for the first time, the activity of early G2-phase checkpoint after low-dose irradiation in normal fibroblasts of these 4 HRS-positive patients and 4 HRS-negative patients and answer the question regarding the role of this checkpoint in normal human cells. The response of the early G2-phase checkpoint was determined by assessment of the progression of irradiated cells into mitosis using the mitotic marker, phosphorylated histone H3. We found evident differences in the activity of the early G2-phase checkpoint between HRS-positive and HRS-negative fibroblasts. In HRS-positive fibroblasts the checkpoint was not triggered and DNA damage was not recognized after doses lower than 0.2Gy resulting in HRS response. On the contrary, in HRS-negative fibroblasts the early G2-phase checkpoint was activated regardless of the dose in the range 0.1-2Gy. In conclusion, although cell cycle phase has no effect on the presence of HRS effect in normal human fibroblasts, the data reported here indicate that HRS response in these cells is associated with the functioning of early G2-phase checkpoint in a threshold-dose dependent manner, similarly as it takes place in most of human tumor and other cells.
authors.affiliation: Department of Applied Radiobiology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology Cracow Branch, 11 Garncarska Street, Cracow 31-115, Poland. Electronic address: z5slonin@cyfronet.pl.
authors.forename: Dorota
authors.initials: D
authors.lastname: Słonina
authors.affiliation: Department of Applied Radiobiology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology Cracow Branch, 11 Garncarska Street, Cracow 31-115, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Gasińska
authors.affiliation: Department of Applied Radiobiology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology Cracow Branch, 11 Garncarska Street, Cracow 31-115, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Biesaga
authors.affiliation: Department of Applied Radiobiology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology Cracow Branch, 11 Garncarska Street, Cracow 31-115, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Janecka
authors.affiliation: Department of Medical Physics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology Cracow Branch, 11 Garncarska Street, Cracow 31-115, Poland.
authors.forename: Damian
authors.initials: D
authors.lastname: Kabat
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D004247:DNA / Q000528:radiation effects; D004249:DNA Damage; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology* / Q000528:radiation effects; D059565:G2 Phase Cell Cycle Checkpoints; D006657:Histones / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism / Q000503:physiopathology; D010766:Phosphorylation; D011836:Radiation Tolerance
chemical_list: D006657:Histones; D004247:DNA
keywords: Early G2-phase checkpoint; Human fibroblasts; Ionizing radiation; Low dose