250: CIP2A–TOPBP1: Mitotic repair via MiDAS and MMEJ

Nieminuszczy J et al., Nature Communications, doi:10.1038/s41467-025-65594-2 - 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. Key terms: CIP2A, TOPBP1, SLX4, MiDAS, MMEJ.

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:
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Article title:
The CIP2A-TOPBP1 axis facilitates mitotic DNA repair via MiDAS and MMEJ

First author:
Nieminuszczy J

Journal:
Nature Communications, doi:10.1038/s41467-025-65594-2

DOI:
10.1038/s41467-025-65594-2

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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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-01-05.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript portions describing the CIP2A-TOPBP1 axis, MiDAS and MMEJ pathways, the SLX4 Thr1260 phosphorylation by CDK1, TOPBP1-SMX interactions, CIP2A’s regulation of Polθ and SMX components, and the BRCA1/2-deficient synthetic lethal context, plus experimental approaches referenced (co-IP/MS, CRISPR knock
- transcript topics: CIP2A-TOPBP1 axis as a mitotic DNA repair hub; MiDAS and SMX complex recruitment to mitotic chromatin; MMEJ and Polθ dependence in mitosis; CDK1-dependent phosphorylation of SLX4 Thr1260 and TOPBP1 interaction; TOPBP1 BRCT1/2-mediated SMX recruitment and AlphaFold modelling; CIP2A upstream regulation of SLX4 and Polθ localization

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- CIP2A-TOPBP1 axis coordinates mitotic DNA repair by promoting MiDAS and MMEJ
- CDK1-dependent phosphorylation of SLX4 at Thr1260 enables TOPBP1 BRCT1/2 interaction and SMX recruitment...