The role of HIPK2 and TBL1 in crosstalk between metabolic signaling and genotoxic stress response

Cellular stress signaling is a critical process in preventing cancer formation. Thus, mammalian cells are highly dependent on sensing and responding to various forms of cellular stress. There is evidence tightly connecting growth control and cancer formation to dysfunctional metabolic pathways, but still little is known about the involved stress mediators. Transcriptional co-factors have been identified as regulatory checkpoints in energy homeostasis. They regulate target gene expression by assembling to multi-protein complexes mediating chromatin-modification. Recent work from our groups point to a novel transcriptional co-factor complex comprising the nuclear exchange factor transducin β-like protein 1 (TBL1) and the stress responsive homeodomain interacting protein kinase 2 (HIPK2), thereby potentially integrating DNA damage response and lipid metabolism.

Here we aim to characterize this complex as well as to discover the relevance of the individual components as potential coordinating checkpoints for metabolic and genotoxic stress response. We demonstrated that TBL1 and HIPK2 physically interact and identified the corresponding domains. We could exclude TBL1 as a phosphorylation target of HIPK2 and further, that TBL1 is involved in regulating HIPK2 expression. However, TBL1 affects HIPK2 protein levels by promoting its proteasomal degradation.

Therefore, we further plan to focus on TBL1, as a component of the hepatic lipid metabolizing pathway and its role in DNA-damage induced stress response on the one hand. On the other we aim to discover the impact of HIPK2 as a checkpoint for stress-induced metabolic pathway control in liver.