| First Author | Kim SH | Year | 2016 |
| Journal | Nucleic Acids Res | Volume | 44 |
| Issue | 20 | Pages | 9667-9680 |
| PubMed ID | 27431323 | Mgi Jnum | J:246737 |
| Mgi Id | MGI:5923475 | Doi | 10.1093/nar/gkw643 |
| Citation | Kim SH, et al. (2016) Tunable regulation of CREB DNA binding activity couples genotoxic stress response and metabolism. Nucleic Acids Res 44(20):9667-9680 |
| abstractText | cAMP response element binding protein (CREB) is a key regulator of glucose metabolism and synaptic plasticity that is canonically regulated through recruitment of transcriptional coactivators. Here we show that phosphorylation of CREB on a conserved cluster of Ser residues (the ATM/CK cluster) by the DNA damage-activated protein kinase ataxia-telangiectasia-mutated (ATM) and casein kinase1 (CK1) and casein kinase2 (CK2) positively and negatively regulates CREB-mediated transcription in a signal dependent manner. In response to genotoxic stress, phosphorylation of the ATM/CK cluster inhibited CREB-mediated gene expression, DNA binding activity and chromatin occupancy proportional to the number of modified Ser residues. Paradoxically, substoichiometric, ATM-independent, phosphorylation of the ATM/CK cluster potentiated bursts in CREB-mediated transcription by promoting recruitment of the CREB coactivator, cAMP-regulated transcriptional coactivators (CRTC2). Livers from mice expressing a non-phosphorylatable CREB allele failed to attenuate gluconeogenic genes in response to DNA damage or fully activate the same genes in response to glucagon. We propose that phosphorylation-dependent regulation of DNA binding activity evolved as a tunable mechanism to control CREB transcriptional output and promote metabolic homeostasis in response to rapidly changing environmental conditions. |
