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PMID:19151705

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Citation

Nishiyama, M, Oshikawa, K, Tsukada, Y, Nakagawa, T, Iemura, S, Natsume, T, Fan, Y, Kikuchi, A, Skoultchi, AI and Nakayama, KI (2009) CHD8 suppresses p53-mediated apoptosis through histone H1 recruitment during early embryogenesis. Nat. Cell Biol. 11:172-82

Abstract

The chromodomain helicase DNA-binding (CHD) family of enzymes is thought to regulate gene expression, but their role in the regulation of specific genes has been unclear. Here we show that CHD8 is expressed at a high level during early embryogenesis and prevents apoptosis mediated by the tumour suppressor protein p53. CHD8 was found to bind to p53 and to suppress its transactivation activity. CHD8 promoted the association of p53 and histone H1, forming a trimeric complex on chromatin that was required for inhibition of p53-dependent transactivation and apoptosis. Depletion of CHD8 or histone H1 resulted in p53 activation and apoptosis. Furthermore, Chd8(-/-) mice died early during embryogenesis, manifesting widespread apoptosis, whereas deletion of p53 ameliorated this developmental arrest. These observations reveal a mode of p53 regulation mediated by CHD8, which may set a threshold for induction of apoptosis during early embryogenesis by counteracting p53 function through recruitment of histone H1.

Links

PubMed PMC3132516 Online version:10.1038/ncb1831

Keywords

Animals; Apoptosis/genetics; Cadherins/genetics; Cell Line; Down-Regulation/genetics; Embryonic Development/genetics; Gene Expression Regulation, Developmental/genetics; HeLa Cells; Histones/genetics; Humans; Macromolecular Substances/metabolism; Mice; Mice, Knockout; Protein Binding/genetics; Repressor Proteins/genetics; Repressor Proteins/metabolism; Tumor Suppressor Protein p53/genetics

Significance

Annotations

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

HUMAN:P53

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q09XV5

F

Seeded From UniProt

complete

MOUSE:CHD8

enables

GO:0002039: p53 binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P04637

F

Seeded From UniProt

complete

MOUSE:CHD8

acts_upstream_of_or_within

GO:2000270: negative regulation of fibroblast apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CHD8

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:CHD8

enables

GO:0003677: DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:CHD8

enables

GO:0042393: histone binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:CHD8

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CHD8

involved_in

GO:0043066: negative regulation of apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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