FLASH degradation in response to UV-C results in histone locus bodies disruption and cell-cycle arrest.
Eucaryotic cell nuclei contain a number of different organelles that are highly dynamic structures and respond to a variety of stimuli. Here we investigated the effect of UV irradiation on a recently identified group of organelles, Histone Locus Bodies. Histone Locus Bodies contain at least two main proteins, FLASH and NPAT, and have been shown to be involved in replication-dependent histone gene transcription. We show that these organelles are disrupted after sublethal irradiation and both FLASH and NPAT are degraded, which in turn results in cell-cycle arrest at the S/G2 transition. The effect on the cell cycle is due to reduced transcription of histone genes and restoring normal histone protein levels by stabilizing histone mRNA allows cells to progress through the cell cycle. This provides a novel mechanism of S-phase arrest in response to DNA damage that potentially allows DNA repair before cells continue into mitosis, and thus prevents transmission of genomic alterations.
Bongiorno-Borbone
L
L
IDI-IRCCS Biochemistry Laboratory, c/o Department of Experimental Medicine, University of Rome Tor Vergata, Roma, Italy.
De Cola
A
A
Barcaroli
D
D
Knight
R A
RA
Di Ilio
C
C
Melino
G
G
De Laurenzi
V
V
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002453:Cell Cycle / Q000528:radiation effects*; D045744:Cell Line, Tumor; D022003:Cell Nucleus Structures / Q000378:metabolism* / Q000528:radiation effects*; D004249:DNA Damage; D016193:G1 Phase / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000528:radiation effects; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D021381:Protein Transport / Q000528:radiation effects; D016196:S Phase / Q000528:radiation effects; D014158:Transcription, Genetic / Q000528:radiation effects; D014466:Ultraviolet Rays; D015854:Up-Regulation / Q000528:radiation effects
D051017:Apoptosis Regulatory Proteins; C485604:CASP8AP2 protein, human; D002135:Calcium-Binding Proteins; C119301:Casp8ap2 protein, mouse; D006657:Histones; D009687:Nuclear Proteins; C068921:p80-coilin; D046988:Proteasome Endopeptidase Complex