Proximity of chromosomal loci that participate in radiation-induced rearrangements in human cells.
Rearrangements involving the RET gene are common in radiation-associated papillary thyroid cancer (PTC). The RET/PTC1 type of rearrangement is an inversion of chromosome 10 mediated by illegitimate recombination between the RET and the H4 genes, which are 30 megabases apart. Here we ask whether despite the great linear distance between them, RET and H4 recombination might be promoted by their proximity in the nucleus. We used two-color fluorescence in situ hybridization and three-dimensional microscopy to map the positions of the RET and H4 loci within interphase nuclei. At least one pair of RET and H4 was juxtaposed in 35% of normal human thyroid cells and in 21% of peripheral blood lymphocytes, but only in 6% of normal mammary epithelial cells. Spatial contiguity of RET and H4 may provide a structural basis for generation of RET/PTC1 rearrangement by allowing a single radiation track to produce a double-strand break in each gene at the same site in the nucleus.
Nikiforova
M N
MN
Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Stringer
J R
JR
Blough
R
R
Medvedovic
M
M
Fagin
J A
JA
Nikiforov
Y E
YE
D000328:Adult; D001940:Breast / Q000166:cytology; D002478:Cells, Cultured; D007446:Chromosome Inversion; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; D004847:Epithelial Cells; D015321:Gene Rearrangement; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007399:Interphase; D008214:Lymphocytes; D009381:Neoplasms, Radiation-Induced / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011505:Protein-Tyrosine Kinases; D011506:Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D011995:Recombination, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013961:Thyroid Gland / Q000166:cytology* / Q000528:radiation effects*; D013964:Thyroid Neoplasms / Q000235:genetics
C088832:CCDC6 protein, human; D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; D015514:Oncogene Proteins, Fusion; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C093573:ret-PTC fusion oncoproteins, human