RESUMEN
Recurrent chromosomal translocations underlie both haematopoietic and solid tumours. Their origin has been ascribed to selection of random rearrangements, targeted DNA damage, or frequent nuclear interactions between translocation partners; however, the relative contribution of each of these elements has not been measured directly or on a large scale. Here we examine the role of nuclear architecture and frequency of DNA damage in the genesis of chromosomal translocations by measuring these parameters simultaneously in cultured mouse B lymphocytes. In the absence of recurrent DNA damage, translocations between Igh or Myc and all other genes are directly related to their contact frequency. Conversely, translocations associated with recurrent site-directed DNA damage are proportional to the rate of DNA break formation, as measured by replication protein A accumulation at the site of damage. Thus, non-targeted rearrangements reflect nuclear organization whereas DNA break formation governs the location and frequency of recurrent translocations, including those driving B-cell malignancies.
Asunto(s)
Linfocitos B/metabolismo , Linfocitos B/patología , Daño del ADN/genética , Translocación Genética/genética , Animales , Linfocitos B/citología , Núcleo Celular/genética , Núcleo Celular/metabolismo , Células Cultivadas , Posicionamiento de Cromosoma , Cromosomas de los Mamíferos/genética , Cromosomas de los Mamíferos/metabolismo , Citidina Desaminasa/deficiencia , Citidina Desaminasa/genética , Citidina Desaminasa/metabolismo , Roturas del ADN de Doble Cadena , Genes myc/genética , Genoma/genética , Cadenas Pesadas de Inmunoglobulina/genética , Ratones , Proteína de Replicación A/metabolismoRESUMEN
BACKGROUND: Alzheimer's disease (AD) remains challenging to diagnose, especially early disease. Having serum AD biomarkers would be of significant interest both in the clinical setting and in drug development efforts. OBJECTIVE: We applied a novel serum proteomic approach to interrogate the low-molecular weight proteome for serum AD biomarkers. METHODS: A discovery study used sera from 58 any-stage AD cases and 55 matched controls analyzed by capillary liquid chromatography-electrospray ionization-tandem mass spectrometry. Candidate biomarkers were statistically modeled and promising biomarkers were retested in a second, blinded confirmatory study (AD casesâ=â68, controlsâ=â57). Biomarkers that replicated in the second study were modeled for the diagnosis of any-stage and very early stage AD. Further, they were chemically identified by tandem MS. RESULTS: The initial discovery study found 59 novel potential AD biomarkers. Thirteen recurred in more than one multi-marker panel. In a second, blinded, confirmatory study, these same biomarkers were retested in separate specimens. In that study, four markers validated comparing controls to patients with any-stage AD and also with very early AD. The four biomarkers with replicable ability to diagnose AD were then chemically identified. CONCLUSION: These results suggest novel serum AD diagnostic biomarkers can be found using this approach.