The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis

Mara De Marco Zompit, Mònica Torres Esteban, Clémence Mooser, Salomé Adam, Silvia Emma Rossi, Alain Jeanrenaud, Pia-Amata Leimbacher, Daniel Fink, Ann-Marie K. Shorrocks, Andrew N. Blackford, Daniel Durocher and Manuel Stucki ()
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Mara De Marco Zompit: University of Zurich and University Hospital Zurich
Mònica Torres Esteban: University of Zurich and University Hospital Zurich
Clémence Mooser: University of Zurich and University Hospital Zurich
Salomé Adam: Mount Sinai Hospital
Silvia Emma Rossi: Mount Sinai Hospital
Alain Jeanrenaud: University of Zurich and University Hospital Zurich
Pia-Amata Leimbacher: University of Zurich and University Hospital Zurich
Daniel Fink: University of Zurich and University Hospital Zurich
Ann-Marie K. Shorrocks: University of Oxford, John Radcliffe Hospital
Andrew N. Blackford: University of Oxford, John Radcliffe Hospital
Daniel Durocher: Mount Sinai Hospital
Manuel Stucki: University of Zurich and University Hospital Zurich

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract The accurate repair of DNA double-strand breaks (DSBs), highly toxic DNA lesions, is crucial for genome integrity and is tightly regulated during the cell cycle. In mitosis, cells inactivate DSB repair in favor of a tethering mechanism that stabilizes broken chromosomes until they are repaired in the subsequent cell cycle phases. How this is achieved mechanistically is not yet understood, but the adaptor protein TOPBP1 is critically implicated in this process. Here, we identify CIP2A as a TOPBP1-interacting protein that regulates TOPBP1 localization specifically in mitosis. Cells lacking CIP2A display increased radio-sensitivity, micronuclei formation and chromosomal instability. CIP2A is actively exported from the cell nucleus in interphase but, upon nuclear envelope breakdown at the onset of mitosis, gains access to chromatin where it forms a complex with MDC1 and TOPBP1 to promote TOPBP1 recruitment to sites of mitotic DSBs. Collectively, our data uncover CIP2A-TOPBP1 as a mitosis-specific genome maintenance complex.

Date: 2022
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DOI: 10.1038/s41467-022-31865-5

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