title: Tunable regulation of CREB DNA binding activity couples genotoxic stress response and metabolism.
abstract: 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.
authors.affiliation: Department of Human Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Sang Hwa
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Human Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Trinh
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Michele Campaigne
authors.initials: MC
authors.lastname: Larsen
authors.affiliation: Department of Human Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Mastrocola
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Colin R
authors.initials: CR
authors.lastname: Jefcoate
authors.affiliation: Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Pierre R
authors.initials: PR
authors.lastname: Bushel
authors.affiliation: Department of Human Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI 53705, USA rstibbetts@wisc.edu.
authors.forename: Randal S
authors.initials: RS
authors.lastname: Tibbetts
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000235:genetics* / Q000378:metabolism*; D004249:DNA Damage; D004734:Energy Metabolism / Q000235:genetics*; D005786:Gene Expression Regulation; D005943:Gluconeogenesis / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C504923:Crtc2 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D014157:Transcription Factors; D004247:DNA; D000242:Cyclic AMP; D064007:Ataxia Telangiectasia Mutated Proteins