Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
Nucleic Acids Res. 2020 Jul 27;48(13):7252-7264. doi: 10.1093/nar/gkaa508.
The DNA damage response is essential to maintain genomic stability, suppress replication stress, and protect against carcinogenesis. The ATR-CHK1 pathway is an essential component of this response, which regulates cell cycle progression in the face of replication stress. PARP14 is an ADP-ribosyltransferase with multiple roles in transcription, signaling, and DNA repair. To understand the biological functions of PARP14, we catalogued the genetic components that impact cellular viability upon loss of PARP14 by performing an unbiased, comprehensive, genome-wide CRISPR knockout genetic screen in PARP14-deficient cells. We uncovered the ATR-CHK1 pathway as essential for viability of PARP14-deficient cells, and identified regulation of DNA replication dynamics as an important mechanistic contributor to the synthetic lethality observed. Our work shows that PARP14 is an important modulator of the response to ATR-CHK1 pathway inhibitors.
DNA 损伤反应对于维持基因组稳定性、抑制复制压力以及预防癌变至关重要。ATR-CHK1 通路是该反应的重要组成部分，它在面对复制压力时调节细胞周期进程。PARP14 是一种具有多种转录、信号转导和 DNA 修复功能的 ADP-ribosyltransferase。为了了解 PARP14 的生物学功能，我们通过在 PARP14 缺陷细胞中进行无偏、全面的全基因组 CRISPR 敲除遗传筛选，对 PARP14 缺失后影响细胞活力的遗传成分进行了编目。我们发现 ATR-CHK1 通路对于 PARP14 缺陷细胞的活力至关重要，并确定了 DNA 复制动力学的调节是观察到的合成致死性的一个重要机制贡献者。我们的工作表明，PARP14 是 ATR-CHK1 通路抑制剂反应的重要调节剂。
