The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1 from DNA double-strand breaks

TY - JOUR

T1 - The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1 from DNA double-strand breaks

AU - Acs, Klara

AU - Luijsterburg, Martijn S

AU - Ackermann, Leena

AU - Salomons, Florian A

AU - Hoppe, Thorsten

AU - Dantuma, Nico P

PY - 2011/12

Y1 - 2011/12

N2 - 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.

AB - 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.

KW - Adenosine Triphosphatases/genetics

KW - Cell Cycle Proteins/genetics

KW - Chromosomal Proteins, Non-Histone/metabolism

KW - DNA Breaks, Double-Stranded

KW - DNA Repair/physiology

KW - DNA-Binding Proteins/metabolism

KW - Epigenesis, Genetic

KW - Histones/metabolism

KW - Humans

KW - Intracellular Signaling Peptides and Proteins/metabolism

KW - Models, Genetic

KW - Nuclear Proteins/metabolism

KW - Tumor Suppressor p53-Binding Protein 1

KW - Ubiquitin-Protein Ligases/metabolism

KW - Ubiquitination

KW - Valosin Containing Protein

U2 - 10.1038/nsmb.2188

DO - 10.1038/nsmb.2188

M3 - Journal article

C2 - 22120668

SN - 1545-9993

VL - 18

SP - 1345

EP - 1350

JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

IS - 12

ER -