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Mecanismos que generan la complejidad del genoma del cáncer a partir de un solo error de división celular
Neil T Umbreit1,2,3, Cheng-Zhong Zhang4,5, Luke D Lynch2,3
1Howard Hughes Medical Institute, Chevy Chase, MD, USA. neilt_umbreit@dfci.harvard.edu david_pellman@dfci.harvard.edu cheng-zhong_zhang@dfci.harvard.edu.
Science (New York, N.Y.)
|April 18, 2020
Resumen
El ciclo de ruptura-fusión-puente (BFB), desencadenado por errores de división celular, impulsa la amplificación genética y la inestabilidad del genoma en el cáncer. Este proceso, que involucra fuerzas de actomiosina y estallidos de replicación de ADN, alimenta la cromotripsis y la evolución del cáncer.
Área de la Ciencia:
- La genética
- Biología del cáncer
- Biología celular
Sus antecedentes:
- El ciclo de ruptura-fusión-puente de cromosomas (BFB) es un mecanismo conocido de inestabilidad del genoma y amplificación génica.
- Los ciclos BFB y la cromotripsis se observan con frecuencia juntos en los genomas del cáncer.
- La cascada mutacional precisa que vincula los ciclos BFB a la cromotripsis no se ha aclarado por completo.
Objetivo del estudio:
- Para aclarar la cascada mutacional que une los ciclos de ruptura-fusión-puente de cromosomas (BFB) a la cromotripsis.
- Identificar los mecanismos celulares que impulsan la acumulación de complejidad genómica durante esta cascada.
- Comprender el papel de las fuerzas de actomiosina y los errores de división celular en el inicio de este proceso.
Principales métodos:
- Investigó el papel de las fuerzas de actomiosina en la ruptura inicial del puente cromosómico.
- Análisis de la replicación aberrante del ADN durante la interfase después de la formación del puente.
- Examinado el daño del ADN y la segregación errónea cromosómica durante la mitosis posterior.
- Observación de la formación de micronúcleos y su papel en la promoción de una mayor cromotripsis.
Principales resultados:
- Las fuerzas de la actomyosina son esenciales para la ruptura inicial de los puentes cromosómicos.
- La replicación interfásica aberrante del ADN puente inicia la acumulación de cromotripsis.
- Un estallido de replicación del ADN durante la mitosis conduce a un daño extenso del ADN.
- La segregación errónea de los cromosomas puente rotos y la formación de micronúcleos promueven una mayor cromotripsis.
Conclusiones:
- Un solo error de división celular, que conduce a la formación de un puente cromosómico, desencadena una cascada que aumenta rápidamente la complejidad genómica.
- Esta cascada vincula los ciclos BFB con la cromotripsis, explicando su co-ocurrencia en el cáncer.
- Las rondas iterativas de esta cascada mutacional contribuyen a la evolución en curso y a la heterogeneidad subclonal observada en muchos cánceres humanos.
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