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PARP1 interacts with WDR5 to enhance target gene recognition and facilitate tumorigenesis

Yali Qin1, Xiaochuan Dong2, Manman Lu1

  • 1School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

Cancer Letters
|May 16, 2024
PubMed

Insights

Poly (ADP-ribose) polymerase-1 (PARP1) interacts with WDR5 to regulate gene expression and chromatin. Combined inhibition of WDR5 and PARP1 significantly hinders cancer cell proliferation, revealing new therapeutic targets.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Research

Background:

  • Poly (ADP-ribose) polymerase-1 (PARP1) is crucial for DNA damage repair.
  • PARP1's role in chromatin recognition and gene expression regulation requires further elucidation.
  • Understanding PARP1's interaction with chromatin modifiers is key to its non-canonical functions.

Purpose of the Study:

  • To investigate the interaction between PARP1 and SET1/MLL complexes, specifically with WDR5.
  • To determine the impact of PARP1 on WDR5 binding and histone methylation at specific gene loci.
  • To explore the therapeutic potential of targeting the PARP1-WDR5 interaction in cancer.

Main Methods:

  • Co-immunoprecipitation assays to confirm protein interactions.
  • Chromatin immunoprecipitation (ChIP) to assess locus-specific binding and histone modifications.
  • Cell proliferation assays to evaluate the combined effect of WDR5 and PARP1 inhibition.

Main Results:

  • PARP1 directly binds to WDR5, a component of SET1/MLL complexes.
  • PARP1 influences locus-specific WDR5 binding and H3K4 methylation without altering global levels.
  • Inhibition of the WDR5 Win site disrupts PARP1-WDR5 interaction and target gene binding.
  • Combined inhibition of WDR5 and PARP1 demonstrates potent anti-proliferative effects in cancer cells.

Conclusions:

  • PARP1 and WDR5 cooperate in chromatin recognition and target gene expression.
  • The WDR5 Win site is critical for PARP1 recruitment to target genes.
  • Targeting the PARP1-WDR5 axis offers a promising strategy for cancer therapy.
Keywords:
Chromatin bindingMLL complexesPARP1TranscriptionWDR5

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