title: Replication stress induces 53BP1-containing OPT domains in G1 cells.
abstract: Chromosomal deletions and rearrangements in tumors are often associated with common fragile sites, which are specific genomic loci prone to gaps and breaks in metaphase chromosomes. Common fragile sites appear to arise through incomplete DNA replication because they are induced after partial replication inhibition by agents such as aphidicolin. Here, we show that in G1 cells, large nuclear bodies arise that contain p53 binding protein 1 (53BP1), phosphorylated H2AX (γH2AX), and mediator of DNA damage checkpoint 1 (MDC1), as well as components of previously characterized OPT (Oct-1, PTF, transcription) domains. Notably, we find that incubating cells with low aphidicolin doses increases the incidence and number of 53BP1-OPT domains in G1 cells, and by chromatin immunoprecipitation and massively parallel sequencing analysis of γH2AX, we demonstrate that OPT domains are enriched at common fragile sites. These findings invoke a model wherein incomplete DNA synthesis during S phase leads to a DNA damage response and formation of 53BP1-OPT domains in the subsequent G1.
authors: The Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, England, UK.
authors: Jeanine A
authors: JA
authors: Harrigan
authors: Rimma
authors: R
authors: Belotserkovskaya
authors: Julia
authors: J
authors: Coates
authors: Daniela S
authors: DS
authors: Dimitrova
authors: Sophie E
authors: SE
authors: Polo
authors: Charles R
authors: CR
authors: Bradshaw
authors: Peter
authors: P
authors: Fraser
authors: Stephen P
authors: SP
authors: Jackson
mesh_terms: D002478:Cells, Cultured; D004261:DNA Replication / Q000235:genetics*; D016193:G1 Phase / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D050811:Octamer Transcription Factor-1 / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics*; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D050811:Octamer Transcription Factor-1; C106703:SNAPC protein complex, human; C498301:TP53BP1 protein, human; D014157:Transcription Factors; D000071857:Tumor Suppressor p53-Binding Protein 1