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Suppressing PARylation by 2',5'-oligoadenylate synthetase 1 inhibits DNA damage-induced cell death

Anna A Kondratova1,2, HyeonJoo Cheon1, Beihua Dong1

  • 1Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.

The EMBO Journal
|April 24, 2020
PubMed

Insights

High expression of 2

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • 2',5'-oligoadenylate synthetase 1 (OAS1) is highly expressed in many cancers, associated with DNA damage resistance.
  • Poly(ADP-ribose) (PAR) synthesis is crucial for DNA repair but excessive PAR accumulation can lead to cell death.

Purpose of the Study:

  • To investigate the role of OAS1 in modulating PAR synthesis and its impact on cancer cell survival following DNA damage.

Main Methods:

  • In vitro enzymatic assays to assess OAS1 activity on PAR.
  • Cellular experiments measuring PAR accumulation and cell viability after DNA-damaging treatments in cells with varying OAS1 expression.

Main Results:

  • OAS1 directly modifies PAR by adding AMP residues in a 2',5' linkage, inhibiting PAR synthesis in vitro.
  • Increased OAS1 expression reduces PAR accumulation in cells and significantly enhances cell viability after DNA damage exposure.

Conclusions:

  • OAS1 attenuates PAR synthesis, thereby preventing cell death pathways activated by excessive PAR accumulation.
  • High OAS1 expression in cancer cells confers a survival advantage against DNA-damaging agents by modulating PAR metabolism.
Keywords:
PARP1PARylationoligoadenylate synthetaseparthanatos

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