TY - JOUR
T1 - Genome-wide CRISPR synthetic lethality screen identifies a role for the ADP-ribosyltransferase PARP14 in DNA replication dynamics controlled by ATR
AU - Dhoonmoon, Ashna
AU - Schleicher, Emily M.
AU - Clements, Kristen E.
AU - Nicolae, Claudia M.
AU - Moldovan, George Lucian
N1 - Funding Information:
We would like to thank Drs Hong-Gang Wang and Robert Brosh for materials and advice; and the following Penn State College of Medicine core facilities: Flow Cytometry, Genomic Analyses and Imaging. We would also like to thank Dr Rose Oughtred and the BioGRID Administration Team for their help with uploading our CRISPR datasets. National Institute of Health [R01ES026184 and R01GM134681 to G.L.M.; F31CA243301 to E.M.S.]. Funding for open access charge: National Institutes of Health. Conflict of interest statement. None declared.
Publisher Copyright:
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
PY - 2020/7/27
Y1 - 2020/7/27
N2 - 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.
AB - 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.
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U2 - 10.1093/nar/gkaa508
DO - 10.1093/nar/gkaa508
M3 - Article
C2 - 32542389
AN - SCOPUS:85088494578
SN - 0305-1048
VL - 48
SP - 7252
EP - 7264
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 13
ER -