Molecular Basis of XRN2-Deficient Cancer Cell Sensitivity to Poly(ADP-ribose) Polymerase Inhibition

R-loops (RNA-DNA hybrids with displaced single-stranded DNA) have emerged as a potent source of DNA damage and genomic instability. The termination of defective RNA polymerase II (RNAPII) is one of the major sources of R-loop formation. 5'-3'-exoribonuclease 2 (XRN2) promotes genome-wide e...

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Bibliographic Details
Published in:	Cancers Vol. 16; no. 3; p. 595
Main Authors:	Viera, Talysa, Abfalterer, Quinn, Neal, Alyssa, Trujillo, Richard, Patidar, Praveen L
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 30-01-2024
Subjects:	Antibodies Breast cancer Cancer Caspase-3 Cell cycle Cell death Cellular stress response DNA DNA damage DNA-directed RNA polymerase Ethylenediaminetetraacetic acid Genes Genetic aspects Genetic transcription Genomes Genomic instability Genomics Hybrids Laboratories Lethality Lung cancer Metabolism Methylene blue Monosaccharides Poly(ADP-ribose) Poly(ADP-ribose) polymerase Prevention Proteins R-loops Ribose RNA RNA polymerase Single-stranded DNA siRNA Sugars Transcription termination Translation Massachusetts St Louis Missouri United States > US DSB repair replication stress PARP1 R-loop XRN2 synthetic lethality
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Summary:	R-loops (RNA-DNA hybrids with displaced single-stranded DNA) have emerged as a potent source of DNA damage and genomic instability. The termination of defective RNA polymerase II (RNAPII) is one of the major sources of R-loop formation. 5'-3'-exoribonuclease 2 (XRN2) promotes genome-wide efficient RNAPII termination, and XRN2-deficient cells exhibit increased DNA damage emanating from elevated R-loops. Recently, we showed that DNA damage instigated by XRN2 depletion in human fibroblast cells resulted in enhanced poly(ADP-ribose) polymerase 1 (PARP1) activity. Additionally, we established a synthetic lethal relationship between XRN2 and PARP1. However, the underlying cellular stress response promoting this synthetic lethality remains elusive. Here, we delineate the molecular consequences leading to the synthetic lethality of XRN2-deficient cancer cells induced by PARP inhibition. We found that XRN2-deficient lung and breast cancer cells display sensitivity to two clinically relevant PARP inhibitors, Rucaparib and Olaparib. At a mechanistic level, PARP inhibition combined with XRN2 deficiency exacerbates R-loop and DNA double-strand break formation in cancer cells. Consistent with our previous findings using several different siRNAs, we also show that XRN2 deficiency in cancer cells hyperactivates PARP1. Furthermore, we observed enhanced replication stress in XRN2-deficient cancer cells treated with PARP inhibitors. Finally, the enhanced stress response instigated by compromised PARP1 catalytic function in XRN2-deficient cells activates caspase-3 to initiate cell death. Collectively, these findings provide mechanistic insights into the sensitivity of XRN2-deficient cancer cells to PARP inhibition and strengthen the underlying translational implications for targeted therapy.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2072-6694 2072-6694
DOI:	10.3390/cancers16030595