TY - JOUR
T1 - KH-like Domains in PARP9/DTX3L and PARP14 Coordinate Protein–Protein Interactions to Promote Cancer Cell Survival
AU - Saleh, Hadil
AU - Liloglou, Triantafillos
AU - Rigden, Daniel J.
AU - Parsons, Jason L.
AU - Grundy, Gabrielle J.
N1 - We thank Mario Niepel and Ribon Therapeutics for sharing the PARP14 inhibitor and negative control, Michael Cohen and Bryce Paschal for sharing PARP14, PARP9, and DTX3L plasmids. GJG was supported by North West Cancer Research fellowship (NWCR CDF2019.05) and HS was funded by NWCR PhD Studentship. JLP is currently supported by funding from the Medical Research Council, UK MRC (MR/V028944/1) and by the National Institutes of Health, NIH (R01CA256854).
PY - 2024/2/15
Y1 - 2024/2/15
N2 - 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.
AB - 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.
U2 - 10.1016/j.jmb.2023.168434
DO - 10.1016/j.jmb.2023.168434
M3 - Article
SN - 0022-2836
VL - 436
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 4
M1 - 168434
ER -
