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CIP2A mediates mitotic recruitment of SLX4/MUS81/XPF to resolve replication stress-induced DNA lesions

Lauren de Haan1, Sietse J Dijt2, Alejandro García-López1

  • 1Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Nature Communications
|December 2, 2025
PubMed

Insights

The CIP2A-TOPBP1 complex resolves incompletely replicated DNA during mitosis by recruiting the SMX complex. This process is vital for chromosome segregation and the survival of BRCA2-deficient cells.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Incompletely replicated DNA poses a threat to chromosome segregation during mitosis.
  • The CIP2A-TOPBP1 complex is known to tether fragmented DNA during mitosis.
  • The role of CIP2A in processing incompletely replicated DNA remained unclear.

Purpose of the Study:

  • To investigate the function of CIP2A in processing incompletely replicated DNA during mitosis.
  • To elucidate the mechanism by which CIP2A-TOPBP1 resolves mitotic DNA lesions.
  • To determine the role of CIP2A and SLX4 in the survival of BRCA2-deficient cells.

Main Methods:

  • Immunofluorescence microscopy to visualize CIP2A-TOPBP1 structures.
  • Recruitment assays for SMX complex members (SLX4, MUS81, XPF-ERCC1).
  • Analysis of BRCA1/2-deficient cells and assessment of cell survival.

Main Results:

  • CIP2A-TOPBP1 forms filamentous structures at sites of incomplete DNA replication during mitosis.
  • These structures facilitate the recruitment of the SMX complex, including SLX4.
  • The C-terminal domain of CIP2A is essential for filament formation and SMX recruitment.
  • CIP2A and SLX4 are recruited to mitotic DNA lesions in BRCA1/2-deficient cells.
  • CIP2A and SLX4 are crucial for the survival and genome stability of BRCA2-deficient cells.

Conclusions:

  • CIP2A-TOPBP1 recruits the SMX complex to resolve mitotic DNA lesions.
  • This resolution is critical for faithful chromosome segregation.
  • CIP2A and SLX4 play essential roles in maintaining the viability of BRCA2-deficient cells.

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