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

•PARP9 and PARP14 are lesser studied ADP-ribosyltransferases implicated in cancer cell survival.•PARP9 and DTX3L regulate PARP14 protein levels therefore depleting PARP9, DTX3L or PARP14 mRNA results in loss of PARP14 protein and a reduction in cancer cell survival through a loss of proliferation and increase in apoptosis.•PARP14′s promotion of cell survival does not depend on its ADP-ribosylation activity but requires a predicted KH domain in the C-terminus region that is necessary for interacting with DTX3L.•A KH-like domain (KHL) was also predicted in PARP9 and five in DTX3L. PARP14 KHL and PARP9 KHL both interact with KHL4 of DTX3L by different means, in a tertiary complex that facilitates PARP14 trans-ADP-ribosylation of PARP9 and DTX3L in vitro.•KHL1 of DTX3L forms a homodimerisation surface that allows a heterodimeric complex to form with PARP9.