Fresh preprint from the lab: CIP2A tetramerization is required for mitotic DNA repair. A fantastic collaboration with @marcelvanvugt.bsky.social. By @laurendehaan.bsky.social, @rebeccaschneeweiss.bsky.social, and colleagues from Groningen, Vienna, Leiden, and Amsterdam 🙌 doi.org/10.64898/202...

Mitotic DNA repair is essential for the survival of cells that face DNA replication and DNA repair stress, as seen in certain cancer types. CIP2A is crucial for the recruitment of repair factors, such as POLQ, to DNA lesions at mitotic chromosomes. We set out to gain mechanistic insights into CIP2A.

We purified full-length human CIP2A and found remarkably long structures: CIP2A rods that form via a short tetrameric antiparallel coiled coil. The tetramerization is crucial for POLQ-mediated signatures of mitotic DNA repair. Interfering with CIP2A tetramerization hypersensitizes HR-deficient cells

More work is needed to unravel how CIP2A, a multimerizing spacer, exactly promotes a functional DNA damage response. One experiment to highlight: to test if CIP2A tetramerization is required and -to some degree- sufficient mitotic DNA repair, we swapped the C-terminal end of human CIP2A..

Comments and questions very much welcome! Here a link again: doi.org/10.64898/202...

This study was spearheaded by talented PhD students Lauren de Haan @laurendehaan.bsky.social , and Rebecca Schneeweiss @rebeccaschneeweiss.bsky.social and supported by many labmembers and collaborators, including the labs of Jos Jonkers @josjonkers.bsky.social and Marcel Tijsterman.

This CIP2A tetramer has a dumbbell shape, with indirect DNA binding capacity at either end, through its binding-partner TOPBP1. This mechanistic insight explains its DNA tethering capacity in mitotic DNA repair.

We show that a small C-terminal domain within CIP2A, at the end of a long coiled-coil domain, allows 2 CIP2A dimers to form a tetramer. Mutations that interfere with CIP2A tetramerization block mitotic DNA repair, and are synthetic lethal in cells with mutant BRCA1/2.

Very pleased to share this new study: In a truly collaborative effort with the lab of Pim Huis in 't Veld @huis.bsky.social, we combined biochemistry with cell biological and genomic approaches to uncover how CIP2A works in mitotic DNA repair. www.biorxiv.org/content/10.6...

CIP2A tetramerization is required for mitotic DNA repair

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 syn...

biorxiv.org

I am truly grateful for the opportunity to contribute to this exciting project revealing that CIP2A tetramerization via its C-terminus is required for DNA repair in mitosis.

@marcelvanvugt.bsky.social · 2mo ago

Very pleased to share this new study: In a truly collaborative effort with the lab of Pim Huis in 't Veld @huis.bsky.social, we combined biochemistry with cell biological and genomic approaches to uncover how CIP2A works in mitotic DNA repair. www.biorxiv.org/content/10.6...