Here we show a correlation between telomere length and organismal sensitivity to ionizing radiation (IR) in mammals. In particular, fifth generation (G5) mouse telomerase RNA (mTR) Ϫ / Ϫ mice, with telomeres 40% shorter than in wild-type mice, are hypersensitive to cumulative doses of gamma rays. 60% of the irradiated G5 mTR Ϫ / Ϫ mice die of acute radiation toxicity in the gastrointestinal tract, lymphoid organs, and kidney. The affected G5 mTR Ϫ / Ϫ mice show higher chromosomal damage and greater apoptosis than similarly irradiated wildtype controls. Furthermore, we show that G5 mTR Ϫ / Ϫ mice show normal frequencies of sister chromatid exchange and normal V(D)J recombination, suggesting that short telomeres do not significantly affect the efficiency of DNA double strand break repair in mammals. The IR-sensitive phenotype of G5 mTR Ϫ / Ϫ mice suggests that telomere function is one of the determinants of radiation sensitivity of whole animals.

These findings identify genes that fulfill some of the requirements of a good exposure biomarker even at low doses, such as sensitivity, reproducibility and simple proportionality with dose.

The data provide evidence that there are a number of genes which seem suitable for biological dosimetry using peripheral blood, including sestrin 1 (SESN1), growth arrest and DNA damage inducible 45 alpha (GADD45A), cyclin-dependent kinase inhibitor 1A (CDKN1A), cyclin G1 (CCNG1), ferredoxin reductase (FDXR), p53 up-regulated mediator of apoptosis (BBC3) and Mdm2 p53 binding protein homolog (MDM2). These biomarkers could potentially be used for triage after large-scale radiological incidents and for monitoring radiation exposure during radiotherapy.

Human lymphocytes in G0 have been irradiated with X-ray doses from 0 to 4.0 Gy. Metaphase chromosomes 2, 3 and 5 and all centromeres were painted using fluorescence in situ hybridization (FISH) probe libraries. Dicentrics, centric rings and acentrics in the whole genome as well as translocations involving the painted chromosomes were recorded. The translocations were subdivided as complete or incomplete. Interstitial insertions and inversions were also noted. The observations were also recorded according to the Protocol for Aberration Identification and Nomenclature Terminology (PAINT) system of scoring. Given that the painted chromosomes comprise 20.4% of the genome it was found that the yield of bicoloured dicentrics was consistent with the yield of dicentrics in the whole genome. The yield of radiation-induced translocations was not significantly higher than that of bicoloured dicentrics. Of the translocations, 60% were complete and it was concluded that the majority of dicentrics and translocations are complete exchanges. Chromosome 5 took part in exchanges marginally more commonly than its length suggests, but it is not known if this is a property of the chromosome or whether it is a donor-dependent observation. The PAINT system of recording rearrangements was examined and the suggested numerical interpretation of this nomenclature was considered to be unsuitable for use in the estimation of dose for cases of accidental overexposure.

Radiation-induced acute myeloid leukemias (AMLs) in the mouse are characterized by chromosome 2 deletions. Previous studies showed that a minimal deleted region (mdr) of approximately 6.5 cM is lost from one homologue in chromosome 2-deleted AMLs. An AML tumor suppressor gene is proposed to map within this mdr. In this study, we refine the mdr to a I cM interval between markers D2Mit126 and D2Mit185 by microsatellite analysis of 21 primary radiation-induced F I AMLs. The construction of a partial yeast artificial chromosome (YAC) contig spanning the mdr and the location of six known genes indicated that the 1 cM mdr is homologous to human 11p11-12, a region implicated in some human AMLs. Screening of five cell lines derived from primary radiation-induced AMLs for homozygous loss of microsatellites and genes mapping within the mdr revealed loss of both copies of the hemopoietic tissue-specific transcription factor Sfpi1(PU.1/Spi1) in one cell line. Studies of primary and F1 AMLs failed to implicate Sfpi1 as the AML tumor suppressor gene. YAC contig construction, together with data suggesting that the critical gene flanks Sfpi1, represents significant progress toward identifying an AML tumor suppressor gene.

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Normal tissue reactions to radiation therapy vary in severity among patients and cannot be accurately predicted, limiting treatment doses. The existence of heritable radiosensitivity syndromes suggests that normal tissue reaction severity is determined, at least in part, by genetic factors and these may be revealed by differences in gene expression. To test this hypothesis, peripheral blood lymphocyte cultures from 22 breast cancer patients with either minimal (11) or very severe acute skin reactions (11) have been used to analyse gene expression. Basal and post-irradiation expression of four radiation-responsive genes (CDKN1A, GADD45A, CCNB1, and BBC3) was determined by quantitative real-time PCR in T-cell cultures established from the two patient groups before radiotherapy. Relative expression levels of BBC3, CCNB1, and GADD45A 2 h following 2 Gy X-rays did not discriminate between groups. However, post-irradiation expression response was significantly reduced for CDKN1A (Po0.002) in severe reactors compared to normal. Prediction of reaction severity of B91% of individuals sampled was achieved using this end point. Analysis of TP53 Arg72Pro and CDKN1A Ser31Arg single nucleotide polymorphisms did not show any significant association with reaction sensitivity. Although these results require confirmation and extension, this study demonstrates the possibility of predicting the severity of acute skin radiation toxicity in simple tests.