Abstract
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.
Highlights
The DNA damage response (DDR) machinery is essential to maintain genomic stability, ensure cellular proliferation and protect against carcinogenesis [1]
In line with the findings in 8988T cells, loss of both PARP14 and CHK1 or DNA2 reduced cellular proliferation in U2OS (Figure 2G) and DLD-1 (Figure 2H) cell lines. These results indicate that CHK1 and DNA2 are essential for proliferation of PARP14-deficient cells
The PARP14 synthetic lethality screen described here identified a number of biological processes with which PARP14 activity has been previously associated
Summary
The DNA damage response (DDR) machinery is essential to maintain genomic stability, ensure cellular proliferation and protect against carcinogenesis [1]. The complex mechanisms employed by the DDR participate in repairing DNA damage, and in attenuating replication stress [2,3]. Arrest of the DNA polymerases at sites of replication blockades can result in collapse of the replication machinery and genomic instability. This leads to downstream phosphorylation of Chk, which induces a broad cellular response resulting in stabilization of the replication fork, suppression of origin firing, and cell cycle arrest [4,5,6]. ATR and CHK1 inhibitors are currently being investigated as anti-cancer drugs, with multiple clinical trials under way [7,8]
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