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MCM8/9 and FANCD2 interact within a shared pathway in response to replication stress caused by DNA crosslinks

Rashini Y Beragama Arachchi1, Desmond C Okafor1, Andrew J Snyder1

  • 1Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798, USA.

DNA Repair
|November 14, 2025
PubMed

Insights

The MCM8/9 helicase complex cooperates with Fanconi anemia (FA) protein FANCD2 to repair DNA interstrand crosslinks. This interaction is crucial for genomic integrity, revealing MCM8/9 as a downstream effector in DNA repair pathways.

Area of Science:

  • Molecular Biology
  • Genetics
  • DNA Repair Mechanisms

Background:

  • Genomic integrity is maintained by proteins like Fanconi anemia (FA) pathway proteins and MCM8/9 helicase complex, especially under replication stress.
  • The precise relationship and functional cooperation between FANCD2 and MCM8/9 in DNA repair remain largely uncharacterized.

Purpose of the Study:

  • To elucidate the functional relationship and interaction between the MCM8/9 helicase complex and FANCD2 in the context of DNA interstrand crosslink (ICL) repair.
  • To determine the molecular mechanisms underlying their cooperation and their roles in maintaining genomic stability.

Main Methods:

  • Immunofluorescence and co-immunoprecipitation assays to investigate protein interactions and localization.
  • Functional assays including γH2AX DNA damage assessment and cell survival studies.
  • Genetic manipulation using knockout and knockdown approaches for MCM8, MCM9, and HROB.

Main Results:

  • MCM8/9 directly interacts with the FANCD2 complex and is recruited to ICL-induced nuclear foci, but independently of FANCD2 monoubiquitination.
  • FANCD2 is essential for MCM8/9 recruitment, while MCM8/9 foci formation requires ATPase activity, the BRCv motif, and HROB, but not for FANCD2 binding.
  • Loss of MCM8/9 or HROB leads to increased FANCD2 foci, suggesting MCM8/9 mitigates replication stress. Combined loss of MCM9 and FANCD2 shows epistatic effects, indicating they function in the same pathway.

Conclusions:

  • MCM8/9 acts as a downstream interactor and effector of FANCD2 in the DNA ICL repair pathway.
  • The findings clarify the functional cooperation between MCM8/9 and FANCD2, highlighting their combined importance in resolving DNA damage and maintaining genomic stability.
Keywords:
FANCD2/IMCM8/9colocalizationcrosslink repairhelicaseinteraction

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