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FIRRM/C1orf112 is synthetic lethal with PICH and mediates RAD51 dynamics

Colin Stok1, Stavroula Tsaridou1, Nathalie van den Tempel1

  • 1Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands.

Cell Reports
|June 22, 2023
PubMed

Insights

Scientists discovered that FIRRM and FIGNL1 proteins are crucial for resolving ultrafine DNA bridges (UFBs) during cell division. Their inactivation leads to DNA damage and a reliance on PICH for cell survival, impacting genome maintenance.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Joint DNA molecules arise from DNA replication and repair.
  • Persistent joint molecules form ultrafine DNA bridges (UFBs) during mitosis, hindering sister chromatid separation.
  • The DNA translocase PICH (ERCC6L) is essential for resolving UFBs.

Purpose of the Study:

  • To identify genes that influence dependency on PICH for resolving UFBs.
  • To elucidate the role of FIRRM and FIGNL1 in mitosis and genome maintenance.

Main Methods:

  • Genome-wide loss-of-function screen to identify PICH dependency factors.
  • Investigated interactions between FIRRM, FIGNL1, and PICH.
  • Assessed the impact of FIRRM and FIGNL1 inactivation on UFBs, RAD51 accumulation, and replication fork dynamics.

Main Results:

  • Identified FIGNL1-interacting regulator of recombination and mitosis (FIRRM) as a key factor in PICH dependency.
  • FIRRM stabilizes the AAA+ ATPase FIGNL1.
  • Inactivation of FIRRM or FIGNL1 causes UFB formation, RAD51 accumulation, and impaired replication fork dynamics.
  • FIRRM and FIGNL1 inactivation leads to genome instability.

Conclusions:

  • FIRRM and FIGNL1 are critical for proper RAD51 dynamics at replication forks.
  • Dysregulation of FIRRM/FIGNL1 leads to persistent DNA lesions and cell viability dependency on PICH.
  • These findings reveal a novel pathway regulating genome maintenance and mitosis.
Keywords:
C1orf112CP: Molecular biologyFIRRMPICHUFBscell cyclegenetic screenmitosisrad51replication

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