The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis

• Published in: Nature communications Vol. 13; no. 1; pp. 4143 - 16
• Main Authors: De Marco Zompit, Mara, Esteban, Mònica Torres, Mooser, Clémence, Adam, Salomé, Rossi, Silvia Emma, Jeanrenaud, Alain, Leimbacher, Pia-Amata, Fink, Daniel, Shorrocks, Ann-Marie K, Blackford, Andrew N, Durocher, Daniel, Stucki, Manuel
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 16.07.2022; Nature Publishing Group UK; Nature Portfolio
• Subjects: Autoantigens - genetics; Autoantigens - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell cycle; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Chromatin; Chromosomal Instability; Chromosomes; Deoxyribonucleic acid; DNA; DNA damage; DNA Repair; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Genomes; Genomic instability; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Localization; Membrane Proteins - genetics; Membrane Proteins - metabolism; Micronuclei; Mitosis; Mitosis - physiology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Proteins; Repair; Sensitivity; Tethering
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31865-5

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.