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Las células cancerosas usan rupturas de ADN autoinfligidas para evadir los límites de crecimiento impuestos por el

Brian D Larsen¹, Jan Benada¹, Philip Yuk Kwong Yung²

¹Biotech Research and Innovation Centre, University of Copenhagen, 2200 N Copenhagen, Denmark.

Science (New York, N.Y.)

|April 28, 2022

Resumen

Las células cancerosas sobreviven a la radioterapia creando roturas temporales del ADN, controladas por la DNasa activada por caspasa (CAD). Esto evita la división celular prematura, pero desactivar la CAD hace que los tumores sean vulnerables al daño del ADN.

Área de la Ciencia:

Biología molecular
Investigación del cáncer
Biología celular

Sus antecedentes:

Las terapias genotóxicas contra el cáncer como la radiación son cruciales, pero a menudo se enfrentan a la resistencia adquirida, lo que lleva a la recurrencia del tumor.
Comprender los mecanismos de supervivencia de las células cancerosas durante el tratamiento es vital para desarrollar terapias más efectivas.

Objetivo del estudio:

Investigar los mecanismos por los que las células cancerosas sobreviven al estrés genotóxico, específicamente la irradiación.
Identificar los actores moleculares clave involucrados en la regulación de las rupturas del ADN durante la terapia contra el cáncer.

Principales métodos:

Análisis de las rupturas de ADN en las células cancerosas expuestas a la radiación.
Identificación de las nucleasas responsables de las lesiones del ADN inducidas por la terapia mediante ensayos moleculares.
Investigación de la regulación de la actividad de la nucleasa por las quinasas de respuesta al daño del ADN.

Principales resultados:

Las células cancerosas limitan la progresión mitótica prematura durante la irradiación mediante el aumento reversible de las rupturas del ADN en todo el genoma.
La DNasa activada por caspasa (CAD) fue identificada como la nucleasa responsable de estas lesiones de nuevo en el ADN, a menudo cerca de los sitios del factor de unión CCCTC (CTCF).
La actividad de la CAD está regulada por la fosforilación por las quinasas de respuesta al daño del ADN, independientemente de la actividad de la caspasa.
La pérdida de la actividad de CAD sensibiliza a las células cancerosas a las rupturas de doble cadena de ADN inducidas por la radiación.

Conclusiones:

Las células cancerosas exhiben una adaptación de supervivencia que implica roturas reguladas del ADN para mitigar el daño inducido por la terapia.
La DNasa activada por caspasa (CAD) juega un papel crítico en esta adaptación, limitando los efectos perjudiciales de la radiación.
La orientación de la actividad de la CAD podría representar una estrategia para superar la radiorresistencia en el tratamiento del cáncer.

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