CIP2A tetramerization is required for mitotic DNA repair

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract DNA lesions that persist in mitosis threaten genome stability. These lesions recruit TOPBP1-CIP2A, a complex crucial to tether and process damaged DNA on mitotic chromosomes. Importantly, CIP2A is synthetic lethal in BRCA1/2 mutant cancer cells. However, mechanistic insight into the function of CIP2A is lacking. Here we provide first structural insights into full-length CIP2A and reveal how CIP2A dimers, 46 nm in length, assemble via conserved C-terminal motifs into dumbbell-like tetramers. DNA repair signatures demonstrate that CIP2A tetramerization is crucial for mitotic DNA repair by polymerase theta (POLQ). Tetramerization of CIP2A is needed to recruit POLQ to mitotic DNA lesions and to prevent micronucleation upon replication-born DNA lesions. Tetramerization-defective CIP2A mutants specifically decrease survival of BRCA1/2 mutant cancer cells in a dominant negative manner. Combined, we demonstrate that CIP2A tetramers are crucial components of a mitotic DNA-tethering and repair scaffold, which processes replication-mediated DNA lesions that persist in mitosis.

Authors 18

1. Lauren de Haan

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ, Groningen, the Netherlands

2. Rebecca Schneeweiss

   University of Vienna · Max Perutz Labs · Vienna Biocenter · Medical University of Vienna

   Affiliation as printed

   Max Perutz Labs, Vienna BioCenter, Dr.-Bohr-Gasse 9, 1030 Vienna, Austria

   University of Vienna, Vienna, Austria

   Vienna BioCenter PhD Program, a Doctoral School of the University of Vienna and the Medical University of Vienna, 1030 Vienna, Austria

3. Marco Barazas Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Albinusdreef 2, 2333ZA, Leiden, the Netherlands

4. Milo L. Kaptein

   The Netherlands Cancer Institute · Oncode Institute

   Affiliation as printed

   Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands

5. Femke J. Bakker

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ, Groningen, the Netherlands

6. Anna Dekker Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Albinusdreef 2, 2333ZA, Leiden, the Netherlands

7. Ekaterina Ovcharenko

   University of Vienna · Max Perutz Labs · Vienna Biocenter

   Affiliation as printed

   Max Perutz Labs, Vienna BioCenter, Dr.-Bohr-Gasse 9, 1030 Vienna, Austria

   University of Vienna, Vienna, Austria

8. Soraya S. Beneddine

   University of Vienna · Max Perutz Labs · Vienna Biocenter

   Affiliation as printed

   Max Perutz Labs, Vienna BioCenter, Dr.-Bohr-Gasse 9, 1030 Vienna, Austria

   University of Vienna, Vienna, Austria

9. Angela Graf

   University of Vienna · Max Perutz Labs · Vienna Biocenter

   Affiliation as printed

   Max Perutz Labs, Vienna BioCenter, Dr.-Bohr-Gasse 9, 1030 Vienna, Austria

   University of Vienna, Vienna, Austria

10. Dimitra Paouneskou

    University of Vienna · Max Perutz Labs · Vienna Biocenter

    Affiliation as printed

    Max Perutz Labs, Vienna BioCenter, Dr.-Bohr-Gasse 9, 1030 Vienna, Austria

    University of Vienna, Vienna, Austria

11. Bert van de Kooij

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ, Groningen, the Netherlands

12. Raimundo Freire

    Universidad de La Laguna · Hospital Universitario de Canarias · Universidad Fernando Pessoa Canarias

    Affiliation as printed

    Instituto de Tecnologías Biomédicas, Centro de Investigaciones Biomédicas de Canarias, Facultad de Medicina, Campus Ciencias de la Salud, Universidad de La Laguna, 38200 Santa Cruz de Tenerife, Spain;

    Unidad de Investigación, Hospital Universitario de Canarias, Instituto de Investigación Sanitaria de Canarias (IISC), La Laguna, 38320 Santa Cruz de Tenerife, Spain

    Universidad Fernando Pessoa Canarias, 35450 Santa Maria de Guia, Spain

13. Verena Jantsch

    University of Vienna · Max Perutz Labs · Vienna Biocenter

    Affiliation as printed

    Max Perutz Labs, Vienna BioCenter, Dr.-Bohr-Gasse 9, 1030 Vienna, Austria

    University of Vienna, Vienna, Austria

14. Jos Jonkers

    The Netherlands Cancer Institute · Oncode Institute

    Affiliation as printed

    Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands

15. H. Rudolf de Boer

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ, Groningen, the Netherlands

16. Marcel Tijsterman Aachen Department of Human Genetics

    Leiden University Medical Center

    Affiliation as printed

    Department of Human Genetics, Leiden University Medical Center, Albinusdreef 2, 2333ZA, Leiden, the Netherlands

17. Marcel A.T.M. van Vugt

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ, Groningen, the Netherlands

18. Pim J. Huis in ’t Veld

    University of Vienna · Max Perutz Labs · Vienna Biocenter

    Affiliation as printed

    Max Perutz Labs, Vienna BioCenter, Dr.-Bohr-Gasse 9, 1030 Vienna, Austria

    University of Vienna, Vienna, Austria