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Genome-wide CRISPR synthetic lethality screen identifies a role for the ADP-ribosyltransferase PARP14 in DNA

Ashna Dhoonmoon1, Emily M Schleicher1, Kristen E Clements1

  • 1Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.

Nucleic Acids Research
|June 17, 2020
PubMed

Insights

Poly (ADP-ribose) polymerase 14 (PARP14) deficiency necessitates the ATR-CHK1 pathway for cell survival. This study reveals PARP14

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • The DNA damage response (DDR) is crucial for maintaining genomic stability and preventing cancer.
  • The ATR-CHK1 pathway is a key regulator of cell cycle progression during replication stress.
  • Poly (ADP-ribose) polymerase 14 (PARP14) is involved in transcription, signaling, and DNA repair.

Purpose of the Study:

  • To identify genetic factors influencing cell viability in the absence of PARP14.
  • To elucidate the functional relationship between PARP14 and the ATR-CHK1 pathway.
  • To understand the role of PARP14 in regulating DNA replication dynamics.

Main Methods:

  • Genome-wide CRISPR knockout genetic screen in PARP14-deficient cells.
  • Analysis of cellular viability upon gene depletion.
  • Investigation of DNA replication dynamics.

Main Results:

  • The ATR-CHK1 pathway was found to be essential for the viability of PARP14-deficient cells.
  • Regulation of DNA replication dynamics contributes to synthetic lethality in PARP14-deficient cells.
  • PARP14 modulates cellular responses to ATR-CHK1 pathway inhibitors.

Conclusions:

  • PARP14 plays a significant role in the DNA damage response and genomic stability.
  • The ATR-CHK1 pathway is synthetically lethal with PARP14 loss, highlighting a potential therapeutic vulnerability.
  • PARP14 is a critical modulator of responses to ATR-CHK1 pathway inhibitors, suggesting its involvement in cancer therapy.

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