MCPH1 is essential for cellular adaptation to the G₂-phase decatenation checkpoint

Cellular checkpoints controlling entry into mitosis monitor the integrity of the DNA and delay mitosis onset until the alteration is fully repaired. However, this canonical response can weaken, leading to a spontaneous bypass of the checkpoint, a process referred to as checkpoint adaptation. Here, we have investigated the contribution of microcephalin 1 (MCPH1), mutated in primary microcephaly, to the decatenation checkpoint, a less-understood G₂ pathway that delays entry into mitosis until chromosomes are properly disentangled. Our results demonstrate that, although MCPH1 function is dispensable for activation and maintenance of the decatenation checkpoint, it is required for the adaptive response that bypasses the topoisomerase II inhibition–mediated G₂ arrest. MCPH1, however, does not confer adaptation to the G₂ arrest triggered by the ataxia telangiectasia mutated—and ataxia telangiectasia and rad3 related-based DNA damage checkpoint. In addition to revealing a new role for MCPH1 in cell cycle control, our study provides new insights into the genetic requirements that allow cellular adaptation to G₂ checkpoints, a process that remains poorly understood.—Arroyo, M., Kuriyama, R., Guerrero, I., Keifenheim, D., Cañuelo, A., Calahorra, J., Sánchez, A., Clarke, D. J., Marchai, J. A. MCPH1 is essential for cellular adaptation to the G₂-phase decatenation checkpoint. FASEB J. 33,8363–8374 (2019). www.fasebj.org.