Genome-wide CRISPR synthetic lethality screen identifies a role for the ADP-ribosyltransferase PARP14 in DNA replication dynamics controlled by ATR.

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. is an ADP-ribosyltransferase with multiple roles in transcription, signaling, and DNA repair. To understand the biological functions of we catalogued the genetic components that impact cellular viability upon loss of Pduanyu3714 by performing an unbiased, comprehensive, genome-wide CRISPR knockout genetic screen in cells. We uncovered the ATR-CHK1 pathway as essential for viability of Pduanyu3714-deficient cells, and identified regulation of DNA replication dynamics as an important mechanistic contributor to the synthetic lethality observed. Our work shows that Pduanyu3714 is an important modulator of the response to ATR-CHK1 pathway inhibitors.

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