The role of ubiquitin-dependent segregase p97 (VCP or Cdc48) in chromatin dynamics after DNA double strand breaks

DNA double strand breaks (DSBs) are the most cytotoxic DNA lesions and, if not repaired, lead to chromosomal rearrangement, genomic instability and cell death. Cells have evolved a complex network of DNA repair and signalling molecules which promptly detect and repair DSBs, commonly known as the DNA...

Full description

Saved in:
Bibliographic Details
Published in:Philosophical transactions of the Royal Society of London. Series B. Biological sciences Vol. 372; no. 1731
Main Authors: Torrecilla, Ignacio, Oehler, Judith, Ramadan, Kristijan
Format: Journal Article
Language:English
Published: England 05.10.2017
Subjects:
Animals
DNA Breaks, Double-Stranded
DNA Repair
Humans
Ubiquitinated Proteins - metabolism
Ubiquitination
Valosin Containing Protein - metabolism
genome stability
CHROMAD
chromatin dynamics
p97 (vcp/cdc48)
DNA double strand breaks
DNA repair
ISSN:1471-2970, 1471-2970
Online Access:Get more information
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:DNA double strand breaks (DSBs) are the most cytotoxic DNA lesions and, if not repaired, lead to chromosomal rearrangement, genomic instability and cell death. Cells have evolved a complex network of DNA repair and signalling molecules which promptly detect and repair DSBs, commonly known as the DNA damage response (DDR). The DDR is orchestrated by various post-translational modifications such as phosphorylation, methylation, ubiquitination or SUMOylation. As DSBs are located in complex chromatin structures, the repair of DSBs is engineered at two levels: (i) at sites of broken DNA and (ii) at chromatin structures that surround DNA lesions. Thus, DNA repair and chromatin remodelling machineries must work together to efficiently repair DSBs. Here, we summarize the current knowledge of the ubiquitin-dependent molecular unfoldase/segregase p97 (VCP in vertebrates and Cdc48 in worms and lower eukaryotes) in DSB repair. We identify p97 as an essential factor that regulates DSB repair. p97-dependent extraction of ubiquitinated substrates mediates spatio-temporal protein turnover at and around the sites of DSBs, thus orchestrating chromatin remodelling and DSB repair. As p97 is a druggable target, p97 inhibition in the context of DDR has great potential for cancer therapy, as shown for other DDR components such as PARP, ATR and CHK1.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
ObjectType-Review-3
content type line 23
ISSN:1471-2970
1471-2970
DOI:10.1098/rstb.2016.0282