KH-like Domains in PARP9/DTX3L and PARP14 Coordinate Protein-Protein Interactions to Promote Cancer Cell Survival.

Saleh, Hadil, Liloglou, Triantafillos ORCID: 0000-0003-0460-1404, Rigden, Daniel J ORCID: 0000-0002-7565-8937, Parsons, Jason L ORCID: 0000-0002-5052-1125 and Grundy, Gabrielle J ORCID: 0000-0003-1506-3664 (2024) KH-like Domains in PARP9/DTX3L and PARP14 Coordinate Protein-Protein Interactions to Promote Cancer Cell Survival. Journal of molecular biology, 436 (4). p. 168434.

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Official URL: http://dx.doi.org/10.1016/j.jmb.2023.168434

Abstract

Certain members of the ADP-ribosyltransferase superfamily (ARTD or PARP enzymes) catalyse ADP-ribosylation in response to cellular stress, DNA damage and viral infection and are upregulated in various tumours. PARP9, its binding partner DTX3L and PARP14 protein levels are significantly correlated in head and neck squamous cell carcinoma (HNSCC) and other tumour types though a mechanism where PARP9/DTX3L regulates PARP14 post-transcriptionally. Depleting PARP9, DTX3L or PARP14 expression in HNSCC or HeLa cell lines decreases cell survival through a reduction of proliferation and an increase in apoptosis. A partial rescue of survival was achieved by expressing a PARP14 truncation containing a predicted eukaryotic type I KH domain. KH-like domains were also found in PARP9 and in DTX3L and contributed to protein-protein interactions between PARP9-DTX3L and PARP14-DTX3L. Homodimerization of DTX3L was also coordinated by a KH-like domain and was disrupted by site-specific mutation. Although, cell survival promoted by PARP14 did not require ADP-ribosyltransferase activity, interaction of DTX3L in vitro suppressed PARP14 auto-ADP-ribosylation and promoted trans-ADP-ribosylation of PARP9 and DTX3L. In summary, we characterised PARP9-DTX3L-PARP14 interactions important to pro-survival signalling in HNSCC cells, albeit in PARP14 catalytically independent fashion.

Item Type:	Article
Uncontrolled Keywords:	Hela Cells, Humans, Head and Neck Neoplasms, Ubiquitin-Protein Ligases, Poly(ADP-ribose) Polymerases, Neoplasm Proteins, Cell Survival, Protein Domains, Squamous Cell Carcinoma of Head and Neck
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	25 Jan 2024 09:12
Last Modified:	01 Mar 2024 17:41
DOI:	10.1016/j.jmb.2023.168434
Open Access URL:	https://doi.org/10.1016/j.jmb.2023.168434
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3178003