Oncotarget

Research Papers:

Complementary CRISPR genome-wide genetic screens in PARP10-knockout and overexpressing cells identify synthetic interactions for PARP10-mediated cellular survival

Jude B. Khatib, Emily M. Schleicher, Lindsey M. Jackson, Ashna Dhoonmoon, George-Lucian Moldovan and Claudia M. Nicolae _

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Oncotarget. 2022; 13:1078-1091. https://doi.org/10.18632/oncotarget.28277

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Abstract

Jude B. Khatib1,*, Emily M. Schleicher1,*, Lindsey M. Jackson1, Ashna Dhoonmoon1, George-Lucian Moldovan1 and Claudia M. Nicolae1

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

* These authors contributed equally to this work

Correspondence to:

Claudia M. Nicolae, email: cmn14@psu.edu

Keywords: PARP10; ATM; CRISPR screens; genome stability; cancer cell proliferation

Received: August 04, 2022     Accepted: September 18, 2022     Published: September 28, 2022

Copyright: © 2022 Khatib et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

PARP10 is a mono-ADP-ribosyltransferase with multiple cellular functions, including proliferation, apoptosis, metabolism and DNA repair. PARP10 is overexpressed in a significant proportion of tumors, particularly breast and ovarian cancers. Identifying genetic susceptibilities based on PARP10 expression levels is thus potentially relevant for finding new targets for precision oncology. Here, we performed a series of CRISPR genome-wide loss-of-function screens in isogenic control and PARP10-overexpressing or PARP10-knockout cell lines, to identify genetic determinants of PARP10-mediated cellular survival. We found that PARP10-overexpressing cells rely on multiple DNA repair genes for survival, including ATM, the master regulator of the DNA damage checkpoint. Moreover, we show that PARP10 impacts the recruitment of ATM to nascent DNA upon replication stress. Finally, we identify the CDK2-Cyclin E1 complex as essential for proliferation of PARP10-knockout cells. Our work identifies a network of functionally relevant PARP10 synthetic interactions, and reveals a set of factors which can potentially be targeted in personalized cancer therapy.


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