Show Notes
️ Episode 250: CIP2A–TOPBP1: Mitotic repair via MiDAS and MMEJ
In this episode of PaperCast Base by Base, we explore This study shows the CIP2A-TOPBP1 complex coordinates two mitotic double-strand break repair pathways, MiDAS and MMEJ, by recruiting SLX4/SMX components and Polθ to mitotic chromatin.
Study Highlights:
TOPBP1 BRCT1/2 binds SLX4 phosphorylated at Thr1260, a CDK1-dependent modification that promotes recruitment of SLX4, MUS81 and ERCC1 to mitotic chromatin to drive MiDAS. CIP2A is required for mitotic chromatin localisation of both TOPBP1 and Polθ, enabling Polθ-dependent MMEJ. Loss of CIP2A impairs both MiDAS and MMEJ, increasing micronuclei, γH2AX and 53BP1 and reducing proliferation under replication stress. Pharmacological Polθ inhibition combined with disruption of the TOPBP1–SLX4 interaction further elevates genome instability and selectively limits growth of BRCA1/2-deficient cells.
Conclusion:
The CIP2A-TOPBP1 axis is a central mitotic DNA repair hub that integrates CDK1-dependent phosphorylation and Polθ recruitment to safeguard genome stability and represents a therapeutic vulnerability in HR-deficient tumors.
Music:
Enjoy the music based on this article at the end of the episode.
Reference:
Nieminuszczy J, Kozik Z, Jakub N, Vorhauser J, Lane KA, Martin PR, Kowalski S, Lecot M, Kanellou A, Mansfeld J, Pearl LH, Oliver AW, Downs JA, Niedzwiedz W, Choudhary JS, Day M, et al. The CIP2A-TOPBP1 axis facilitates mitotic DNA repair via MiDAS and MMEJ. Nature Communications. 2025;16:10623. https://doi.org/10.1038/s41467-025-65594-2
License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
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Episode link: https://basebybase.castos.com/episodes/cip2a-topbp1-mitotic-repair
Episode Slug: cip2a-topbp1-mitotic-repair
Keywords: CIP2A, TOPBP1, SLX4, MiDAS, MMEJ
