title: FLASH is essential during early embryogenesis and cooperates with p73 to regulate histone gene transcription.
abstract: Replication-dependent histone gene expression is a fundamental process occurring in S-phase under the control of the cyclin-E/CDK2 complex. This process is regulated by a number of proteins, including Flice-Associated Huge Protein (FLASH) (CASP8AP2), concentrated in specific nuclear organelles known as HLBs. FLASH regulates both histone gene transcription and mRNA maturation, and its downregulation in vitro results in the depletion of the histone pull and cell-cycle arrest in S-phase. Here we show that the transcription factor p73 binds to FLASH and is part of the complex that regulates histone gene transcription. Moreover, we created a novel gene trap to disrupt FLASH in mice, and we show that homozygous deletion of FLASH results in early embryonic lethality, owing to arrest of FLASH(-/-) embryos at the morula stage. These results indicate that FLASH is an essential, non-redundant regulator of histone transcription and cell cycle during embryogenesis.
authors: IDI-IRCCS Biochemistry Laboratory, c/o Department of Experimental Medicine, University of Rome Tor Vergata, Roma, Italy.
authors: A
authors: A
authors: De Cola
authors: L
authors: L
authors: Bongiorno-Borbone
authors: E
authors: E
authors: Bianchi
authors: D
authors: D
authors: Barcaroli
authors: E
authors: E
authors: Carletti
authors: R A
authors: RA
authors: Knight
authors: C
authors: C
authors: Di Ilio
authors: G
authors: G
authors: Melino
authors: C
authors: C
authors: Sette
authors: V
authors: V
authors: De Laurenzi
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005804:Genes, Lethal / Q000235:genetics; D045325:HCT116 Cells; D057809:HEK293 Cells; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C485604:CASP8AP2 protein, human; D002135:Calcium-Binding Proteins; C119301:Casp8ap2 protein, mouse; D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins