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PMID:19303849

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Citation

Wong, RH, Chang, I, Hudak, CS, Hyun, S, Kwan, HY and Sul, HS (2009) A role of DNA-PK for the metabolic gene regulation in response to insulin. Cell 136:1056-72

Abstract

Fatty acid synthase (FAS) is a central enzyme in lipogenesis and transcriptionally activated in response to feeding and insulin signaling. The transcription factor USF is required for the activation of FAS transcription, and we show here that USF phosphorylation by DNA-PK, which is dephosphorylated by PP1 in response to feeding, triggers a switch-like mechanism. Under fasting conditions, USF-1 is deacetylated by HDAC9, causing promoter inactivation. In contrast, feeding induces the recruitment of DNA-PK to USF-1 and its phosphorylation, which then allows recruitment of P/CAF, resulting in USF-1 acetylation and FAS promoter activation. DNA break/repair components associated with USF induce transient DNA breaks during FAS activation. In DNA-PK-deficient SCID mice, feeding-induced USF-1 phosphorylation/acetylation, DNA breaks, and FAS activation leading to lipogenesis are impaired, resulting in decreased triglyceride levels. Our study demonstrates that a kinase central to the DNA damage response mediates metabolic gene activation.

Links

PubMed PMC2768498 Online version:10.1016/j.cell.2008.12.040

Keywords

Acetylation; Animals; Cell Line, Tumor; DNA-Activated Protein Kinase/metabolism; Eating/physiology; Fasting/metabolism; Fatty Acid Synthetase Complex/metabolism; Histone Deacetylases/metabolism; Humans; Insulin/metabolism; Mice; Mice, SCID; Phosphorylation; Promoter Regions, Genetic; Repressor Proteins/metabolism; Upstream Stimulatory Factors/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:PARP1

enables

GO:0008134: transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P22415

F

Seeded From UniProt

complete

HUMAN:PARP1

involved_in

GO:0032869: cellular response to insulin stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PARP1

part_of

GO:0005667: transcription regulator complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:XRCC6

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P78527

F

Seeded From UniProt

complete

HUMAN:XRCC5

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P78527

F

Seeded From UniProt

complete

HUMAN:USF1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q92831

F

Seeded From UniProt

complete

HUMAN:USF1

enables

GO:0019899: enzyme binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P09874

F

Seeded From UniProt

complete

HUMAN:USF1

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P78527

F

Seeded From UniProt

complete

HUMAN:USF1

involved_in

GO:0032869: cellular response to insulin stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:USF1

enables

GO:0042826: histone deacetylase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9UKV0

F

Seeded From UniProt

complete

HUMAN:USF1

part_of

GO:0005667: transcription regulator complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:USF1

involved_in

GO:0045990: carbon catabolite regulation of transcription

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PRKDC

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P12956

F

Seeded From UniProt

complete

HUMAN:PRKDC

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P13010

F

Seeded From UniProt

complete

HUMAN:PRKDC

part_of

GO:0005667: transcription regulator complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:KAT2B

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P22415

F

Seeded From UniProt

complete

HUMAN:HDAC9

enables

GO:0008134: transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P22415

F

Seeded From UniProt

complete

HUMAN:HDAC9

involved_in

GO:0032869: cellular response to insulin stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HDAC9

part_of

GO:0005667: transcription regulator complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:KAT2B

enables

GO:0004468: lysine N-acetyltransferase activity, acting on acetyl phosphate as donor

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:KAT2B

involved_in

GO:0018394: peptidyl-lysine acetylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KAT2B

involved_in

GO:0032869: cellular response to insulin stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PRKDC

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PRKDC

involved_in

GO:0032869: cellular response to insulin stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PRKDC

involved_in

GO:0018105: peptidyl-serine phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PRKDC

enables

GO:0008134: transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P22415

F

Seeded From UniProt

complete

HUMAN:PRKDC

part_of

GO:0005667: transcription factor complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PRKDC

enables

GO:0004674: protein serine/threonine kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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