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

Abstract：

: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.

journal_name

Nat Cell Biol

journal_title

Nature cell biology

authors

Meerang M,Ritz D,Paliwal S,Garajova Z,Bosshard M,Mailand N,Janscak P,Hübscher U,Meyer H,Ramadan K

doi

10.1038/ncb2367

subject

Has Abstract

pub_date

2011-10-23 00:00:00

pages

1376-82

issue

11

eissn

1465-7392

issn

1476-4679

pii

ncb2367

journal_volume

13

pub_type

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