Parp6, a member of the poly-ADP-ribose polymerase (PARP) family, is a neuronally enriched mono-ADP-ribosyltransferase. It is involved in various biological processes such as microtubule regulation, NAD + metabolism, and may play roles in multiple signaling pathways like Wnt/β -catenin, NF -κB, and those related to cell cycle control [2,4,7-9]. Genetic models, especially knockout mouse models, are crucial for studying its functions.

In knockout mouse models, homozygous Parp6 truncated variant (Parp6TR) lacking catalytic activity die perinatally, suggesting Parp6 catalytic activity is essential for postnatal survival [1]. In patients, PARP6 mutations are associated with neurodevelopmental disorders like microencephaly, intellectual disabilities, and epilepsy [1]. In cancer research, in gastric cancer, PARP6 promotes cell proliferation, migration, and invasion by positively regulating Survivin [2]. Conversely, in hepatocellular carcinoma, PARP6 suppresses proliferation and metastasis by degrading XRCC6 to regulate the Wnt/β -catenin pathway [3]. In colorectal cancer, it acts as a tumor suppressor by down-regulating Survivin expression [4]. Pharmacological inhibition of PARP6 in breast cancer triggers multipolar spindle formation and has antitumor effects, with Chk1 identified as a substrate [5].

In conclusion, Parp6 is an essential gene with diverse functions. Its catalytic activity is crucial for postnatal survival in mice and normal neuronal function in humans. In cancer, it can act as either an oncogene or a tumor suppressor depending on the cancer type. Mouse models, especially those with Parp6 loss-of-function, have significantly contributed to understanding its role in neurodevelopmental disorders and cancer.