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.
Bibliographical noteFunding Information:
The authors express gratitude to H. Neitzel (Charite Virchow-Klinikum Hospital, Berlin, Germany) for providing the lymphoblast cell lines used in this study, G. Marques (University of Minnesota?Minneapolis, Minneapolis, MN, USA) for technical assistance, and J. F. GimenezAbi?n [Centre for Biological Research (CIB), Madrid, Spain] and V. Rodriguez-Bravo (Sidney Kimmel Cancer Center, Baltimore, MD, USA) for helpful discussions. Technical and human support provided by Centro de Instrumentaci?n Cient?fico-T?cnica [CICT; Universidad de Ja?n, Ministry of Economy and Competitiveness (MINECO), Junta de Andaluc?a, Federaci?n Espa?ola de Enfermedades Raras (FEDER)] is gratefully acknowledged. This work was supported by Junta de Andaluc?a (funding program Ayudas a Grupos de Investigaci?n, BIO 220). MA. was provided with travelling grants to perform short-term stays at the University of Minnesota by EMBO and Escuela de Doctorado (UJA), respectively. Research at the laboratory of R.K. was financially supported by the National Science Foundation (MCB1140033). Studies performed in the laboratory of D.J.C. were funded by U.S. National Institutes of Health (NIH), National Institute of General Medical Sciences Grants R01GM112793 and R01GM130858. The authors declare no conflicts of interest.
- cell cycle control
- checkpoint adaptation
- chromosome condensation
- topoisomerase II