The ubiquitin-selective segregase VCP/p97 orchestrates the response to DNA double-strand breaks

TY - JOUR

T1 - The ubiquitin-selective segregase VCP/p97 orchestrates the response to DNA double-strand breaks

AU - Meerang, Mayura

AU - Ritz, Danilo

AU - Paliwal, Shreya

AU - Garajova, Zuzana

AU - Bosshard, Matthias

AU - Mailand, Niels

AU - Janscak, Pavel

AU - Hübscher, Ulrich

AU - Meyer, Hemmo

AU - Ramadan, Kristijan

PY - 2011/11

Y1 - 2011/11

N2 - Unrepaired DNA double-strand breaks (DSBs) cause genetic instability that leads to malignant transformation or cell death. Cells respond to DSBs with the ordered recruitment of signalling and repair proteins to the site of lesion. Protein modification with ubiquitin is crucial for the signalling cascade, but how ubiquitylation coordinates the dynamic assembly of these complexes is poorly understood. Here, we show that the human ubiquitin-selective protein segregase p97 (also known as VCP; valosin-containing protein) cooperates with the ubiquitin ligase RNF8 to orchestrate assembly of signalling complexes and efficient DSB repair after exposure to ionizing radiation. p97 is recruited to DNA lesions by its ubiquitin adaptor UFD1-NPL4 and Lys-48-linked ubiquitin (K48-Ub) chains, whose formation is regulated by RNF8. p97 subsequently removes K48-Ub conjugates from sites of DNA damage to orchestrate proper association of 53BP1, BRCA1 and RAD51, three factors critical for DNA repair and genome surveillance mechanisms. Impairment of p97 activity decreases the level of DSB repair and cell survival after exposure to ionizing radiation. These findings identify the p97-UFD1-NPL4 complex as an essential factor in ubiquitin-governed DNA-damage response, highlighting its importance in guarding genome stability.

AB - Unrepaired DNA double-strand breaks (DSBs) cause genetic instability that leads to malignant transformation or cell death. Cells respond to DSBs with the ordered recruitment of signalling and repair proteins to the site of lesion. Protein modification with ubiquitin is crucial for the signalling cascade, but how ubiquitylation coordinates the dynamic assembly of these complexes is poorly understood. Here, we show that the human ubiquitin-selective protein segregase p97 (also known as VCP; valosin-containing protein) cooperates with the ubiquitin ligase RNF8 to orchestrate assembly of signalling complexes and efficient DSB repair after exposure to ionizing radiation. p97 is recruited to DNA lesions by its ubiquitin adaptor UFD1-NPL4 and Lys-48-linked ubiquitin (K48-Ub) chains, whose formation is regulated by RNF8. p97 subsequently removes K48-Ub conjugates from sites of DNA damage to orchestrate proper association of 53BP1, BRCA1 and RAD51, three factors critical for DNA repair and genome surveillance mechanisms. Impairment of p97 activity decreases the level of DSB repair and cell survival after exposure to ionizing radiation. These findings identify the p97-UFD1-NPL4 complex as an essential factor in ubiquitin-governed DNA-damage response, highlighting its importance in guarding genome stability.

KW - Adenosine Triphosphatases

KW - BRCA1 Protein

KW - Cell Cycle Proteins

KW - Cell Line, Tumor

KW - Cell Nucleus

KW - Cell Survival

KW - DNA Breaks, Double-Stranded

KW - DNA Repair

KW - DNA-Binding Proteins

KW - Dose-Response Relationship, Radiation

KW - Genomic Instability

KW - HEK293 Cells

KW - Humans

KW - Intracellular Signaling Peptides and Proteins

KW - Nuclear Proteins

KW - Protein Processing, Post-Translational

KW - Protein Transport

KW - Proteins

KW - RNA Interference

KW - Signal Transduction

KW - Time Factors

KW - Transfection

KW - Ubiquitination

U2 - 10.1038/ncb2367

DO - 10.1038/ncb2367

M3 - Journal article

C2 - 22020440

SN - 1465-7392

VL - 13

SP - 1376

EP - 1382

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 11

ER -