title: The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1 from DNA double-strand breaks.
abstract: The accumulation of the human tumor suppressor 53BP1 at DNA damage sites requires the ubiquitin ligases RNF8 and RNF168. As 53BP1 recognizes dimethylated Lys20 in histone H4 (H4K20me2), the requirement for RNF8- and RNF168-mediated ubiquitylation has been unclear. Here we show that RNF8-mediated ubiquitylation facilitates the recruitment of the AAA-ATPase valosin-containing protein (VCP, also known as p97) and its cofactor NPL4 to sites of double-strand breaks. RIDDLE cells, which lack functional RNF168, also show impaired recruitment of VCP to DNA damage. The ATPase activity of VCP promotes the release of the Polycomb protein L3MBTL1 from chromatin, which also binds the H4K20me2 histone mark, thereby facilitating 53BP1 recruitment. Consistent with this, nematodes lacking the VCP orthologs CDC-48.1 or CDC-48.2, or cofactors UFD-1 or NPL-4, are highly sensitive to ionizing radiation. Our data suggest that human RNF8 and RNF168 promote VCP-mediated displacement of L3MBTL1 to unmask 53BP1 chromatin binding sites.
authors: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors: Klara
authors: K
authors: Acs
authors: Martijn S
authors: MS
authors: Luijsterburg
authors: Leena
authors: L
authors: Ackermann
authors: Florian A
authors: FA
authors: Salomons
authors: Thorsten
authors: T
authors: Hoppe
authors: Nico P
authors: NP
authors: Dantuma
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000378:metabolism; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism / Q000502:physiology*; D054875:Ubiquitination; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C120887:L3MBTL1 protein, human; C514112:NPLOC4 protein, human; D009687:Nuclear Proteins; C486521:RNF8 protein, human; D012097:Repressor Proteins; C498301:TP53BP1 protein, human; D025521:Tumor Suppressor Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; C535210:RNF168 protein, human; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein