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Fort Collins, CO, United States

Hagelstrom R.T.,Colorado State University | Hagelstrom R.T.,Translational Genomics Research Institute | Blagoev K.B.,National Science Foundation | Blagoev K.B.,University of Cambridge | And 3 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

Werner syndrome and Bloom syndrome result from defects in the RecQ helicases Werner (WRN) and Bloom (BLM), respectively, and display premature aging phenotypes. Similarly, XFE progeroid syndrome results from defects in the ERCC1-XPF DNA repair endonuclease. To gain insight into the origin of cellular senescence and human aging, we analyzed the dependence of sister chromatid exchange (SCE) frequencies on location [i.e., genomic (G-SCE) vs. telomeric (T-SCE) DNA] in primary human fibroblasts deficient in WRN, BLM, or ERCC1-XPF. Consistent with our other studies, we found evidence of elevated T-SCE in telomerase-negative but not telomerasepositive backgrounds. In telomerase-negative WRN-deficient cells, T-SCE - but not G-SCE - frequencies were significantly increased compared with controls. In contrast, SCE frequencies were significantly elevated in BLM-deficient cells irrespective of genome location. In ERCC1-XPF-deficient cells, neither T- nor G-SCE frequencies differed from controls. A theoretical model was developed that allowed an in silico investigation into the cellular consequences of increased T-SCE frequency. The model predicts that in cells with increased T-SCE, the onset of replicative senescence is dramatically accelerated even though the average rate of telomere loss has not changed. Premature cellular senescence may act as a powerful tumor-suppressor mechanism in telomerase-deficient cells with mutations that cause T-SCE levels to rise. Furthermore, T-SCE-driven premature cellular senescencemay be a factor contributing to accelerated aging in Werner and Bloom syndromes, but not XFE progeroid syndrome. Source

Colorado State University and Kromatid | Date: 2011-10-11

A method and a kit for the identification of chromosomal inversions are described. Chromosomal inversions are difficult to detect unless they are quite large. The improved ability to detect chromosomal inversions is important to a number of medical applications, such as cancer and birth defects, as examples. Reporter species are attached to oligonucleotide strands designed such that they may hybridize to portions of only one of a pair of single-stranded sister chromatids prepared by the CO-FISH procedure, as an example. If an inversion has occurred, these marker probes will be detected on the sister chromatid at the same location as the inversion on the first chromatid.

Kromatid and Colorado State University | Date: 2011-05-13

Methods, compositions, and assays are described which are useful in identifying point mutations, identifying cancer cells, and diagnosing cancer.

Agency: National Aeronautics and Space Administration | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 600.00K | Year: 2010

We propose the continued development of a novel approach to the detection of chromosomal inversions. Transmissible chromosome aberrations (translocations and inversions) have profound genetic effects, such as disrupting regulatory sequences that control gene expression, or creating genetic chimeras. These chromosome aberrations play a causative role in cancer, and ionizing radiation is one of the most efficient agents known to induce them. As such, chromosome aberrations are relevant to three NASA needs, biodosimetry, analysis of astronaut lymphocytes for cumulative radiation damage, and space radiation risk modeling. Of all structural chromosomal anomalies, inversions – a reversal of orientation of material within a chromosome – are the most difficult to detect. This is especially true of small inversions, most of which are invisible to all current cytogenetic techniques. Yet small inversions are likely the most transmissible (nonlethal) form of chromosomal damage, so they persist for long periods. This is a useful feature for retrospective biodosimetry, and may also prove to be useful as an indicator of radiation quality.. In Phase 1 we demonstrated the use of a human chromosome 3, partial chromatid paint to detect a known inversion. During Phase 2, we will continue to improve the efficiency of the technology, an essential goal for commercialization (Phase 3) ultimately creating an improved and complete chromatid paint for chromosome 3. Finally, we will test the chromosome 3 'chromatid paint's' ability to detect radiation-induced inversions, and establish their frequency. The technology readiness level at the end of the Phase 2 contract is expected to be 5, i.e. validated in laboratory and relevant environments.

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