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FANCJ promotes PARP1 activity during DNA replication that is essential in BRCA1 deficient cells

Ke Cong1, Nathan MacGilvary1, Silviana Lee1

  • 1Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

Nature Communications
|March 24, 2024
PubMed

Insights

Poly (ADP-ribose) polymerase inhibitors (PARPi) effectiveness depends on FANCJ DNA helicase and S-phase PARP1 activity. FANCJ loss impacts PARPi resistance, especially in BRCA1-deficient cells, highlighting PARP1

Area of Science:

  • DNA repair mechanisms
  • Cancer therapeutics
  • Molecular oncology

Background:

  • Poly (ADP-ribose) polymerase inhibitors (PARPi) are crucial cancer drugs.
  • FANCJ DNA helicase is essential for PARPi efficacy.
  • The precise role of FANCJ in PARP1 inhibition and trapping is not fully understood.

Purpose of the Study:

  • To elucidate the relationship between FANCJ, PARP1 activity, and PARPi effectiveness.
  • To investigate how FANCJ deficiency impacts PARPi sensitivity and resistance.
  • To explore the role of S-phase PARP1 activity in PARPi-induced DNA damage.

Main Methods:

  • Cellular assays to assess PARPi sensitivity and DNA gap formation.
  • Investigating protein-protein interactions (FANCJ-MLH1).
  • Gene depletion studies (MSH2, BRCA1) to modulate cellular responses.

Main Results:

  • PARPi effectiveness is dependent on S-phase PARP1 activity, which is reduced in FANCJ-deficient cells.
  • G-quadruplexes sequester PARP1 and MSH2 in FANCJ-deficient cells, reducing PARP1 activity.
  • Loss of FANCJ-MLH1 interaction decreases PARP1 activity, but MSH2 depletion restores PARPi sensitivity.
  • FANCJ loss confers PARPi resistance in cells prone to PARP1 trapping, but mimics PARP1 loss in BRCA1-deficient cells.

Conclusions:

  • PARPi efficacy is critically dependent on FANCJ-mediated S-phase PARP1 activity.
  • Distinct mechanisms of PARP1 sequestration and trapping contribute to differential PARPi responses.
  • Understanding FANCJ's role is vital for optimizing PARPi therapy, particularly in BRCA1-deficient cancers.

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