Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA.
EMBO J. 2020 Jun 2;39(11):e101573. doi: 10.15252/embj.2019101573. Epub 2020 Apr 23.
High expression of 2',5'-oligoadenylate synthetase 1 (OAS1), which adds AMP residues in 2',5' linkage to a variety of substrates, is observed in many cancers as a part of the interferon-related DNA damage resistance signature (IRDS). Poly(ADP-ribose) (PAR) is rapidly synthesized from NAD at sites of DNA damage to facilitate repair, but excessive PAR synthesis due to extensive DNA damage results in cell death by energy depletion and/or activation of PAR-dependent programmed cell death pathways. We find that OAS1 adds AMP residues in 2',5' linkage to PAR, inhibiting its synthesis in vitro and reducing its accumulation in cells. Increased OAS1 expression substantially improves cell viability following DNA-damaging treatments that stimulate PAR synthesis during DNA repair. We conclude that high expression of OAS1 in cancer cells promotes their ability to survive DNA damage by attenuating PAR synthesis and thus preventing cell death.
2',5'-寡聚腺苷酸合成酶 1（OAS1）的高表达，它将 AMP 残基添加到各种底物的 2',5' 连接中，是许多癌症中干扰素相关 DNA 损伤抵抗特征（IRDS）的一部分。聚（ADP-核糖）（PAR）在 DNA 损伤部位从 NAD 迅速合成，以促进修复，但由于广泛的 DNA 损伤导致的过多 PAR 合成会导致细胞死亡，这是由于能量耗竭和/或激活 PAR 依赖性程序性细胞死亡途径所致。我们发现 OAS1 将 AMP 残基添加到 PAR 的 2',5' 连接中，在体外抑制其合成并减少其在细胞中的积累。在 DNA 修复过程中刺激 PAR 合成的 DNA 损伤处理后，OAS1 表达增加可显著提高细胞活力。我们的结论是，癌细胞中 OAS1 的高表达通过减弱 PAR 合成从而防止细胞死亡来促进其在 DNA 损伤后存活的能力。
