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RYBP Sensitizes Cancer Cells to PARP Inhibitors by Regulating ATM Activity

Deanna V Maybee1, Alexandra Maria Psaras1, Tracy A Brooks1

  • 1Department of Pharmaceutical Sciences, SUNY Binghamton University School of Pharmacy and Pharmaceutical Sciences, Binghamton, NY 13790, USA.

International Journal of Molecular Sciences
|October 14, 2022
PubMed

Insights

Ring1 and YY1 Binding Protein (RYBP) inhibits DNA damage response by blocking ATM kinase activity. This sensitization of cancer cells to PARP inhibitors and hindrance of cancer cell migration offers new therapeutic strategies.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Cancer Research

Background:

  • Ring1 and YY1 Binding Protein (RYBP) is a non-canonical Polycomb Repressive Complex 1 (PRC1) member involved in transcriptional regulation and DNA damage response.
  • RYBP inhibits Breast Cancer gene 1 (BRCA1) complex recruitment to DNA damage sites via K63-linked ubiquitin chains.

Purpose of the Study:

  • To investigate the role of RYBP in the DNA damage response, specifically its effect on ATM kinase activity and recruitment.
  • To determine the therapeutic implications of RYBP expression in cancer cells, including sensitivity to PARP inhibitors and impact on metastasis.

Main Methods:

  • Overexpression of RYBP in cancer cells.
  • Assessment of ATM kinase activity through Chk2 phosphorylation.
  • Evaluation of cancer cell response to PARP and ATM inhibitors.
  • Analysis of cancer cell migration.

Main Results:

  • Overexpression of RYBP inhibits ATM kinase activity and its recruitment to DNA damage sites.
  • RYBP-expressing cells exhibit reduced Chk2 phosphorylation after DNA damage.
  • RYBP sensitizes cancer cells to poly-ADP-ribose polymerase (PARP) inhibitors, but abrogates the synergy between PARP and ATM inhibitors.
  • RYBP hinders cancer cell migration, partly due to ATM inhibition.

Conclusions:

  • RYBP acts as an inhibitor of ATM kinase in the DNA damage response.
  • RYBP expression can sensitize cancer cells to DNA damaging agents like PARP inhibitors.
  • RYBP's inhibition of ATM contributes to reduced cancer cell migration and metastasis.
Keywords:
DNA damage response (DDR)Ring1 and YY1 Binding Protein (RYBP)ataxia telangiectasia mutated (ATM)checkpoint kinase 2 (Chk2)poly-ADP-ribose polymerase (PARP)

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