| RRC ID |
53460
|
| 著者 |
Franz A, Pirson PA, Pilger D, Halder S, Achuthankutty D, Kashkar H, Ramadan K, Hoppe T.
|
| タイトル |
Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard DNA replication fork progression.
|
| ジャーナル |
Nat Commun
|
| Abstract |
The coordinated activity of DNA replication factors is a highly dynamic process that involves ubiquitin-dependent regulation. In this context, the ubiquitin-directed ATPase CDC-48/p97 recently emerged as a key regulator of chromatin-associated degradation in several of the DNA metabolic pathways that assure genome integrity. However, the spatiotemporal control of distinct CDC-48/p97 substrates in the chromatin environment remained unclear. Here, we report that progression of the DNA replication fork is coordinated by UBXN-3/FAF1. UBXN-3/FAF1 binds to the licensing factor CDT-1 and additional ubiquitylated proteins, thus promoting CDC-48/p97-dependent turnover and disassembly of DNA replication factor complexes. Consequently, inactivation of UBXN-3/FAF1 stabilizes CDT-1 and CDC-45/GINS on chromatin, causing severe defects in replication fork dynamics accompanied by pronounced replication stress and eventually resulting in genome instability. Our work identifies a critical substrate selection module of CDC-48/p97 required for chromatin-associated protein degradation in both Caenorhabditis elegans and humans, which is relevant to oncogenesis and aging.
|
| 巻・号 |
7
|
| ページ |
10612
|
| 公開日 |
2016-2-4
|
| DOI |
10.1038/ncomms10612
|
| PII |
ncomms10612
|
| PMID |
26842564
|
| PMC |
PMC4743000
|
| MeSH |
Adaptor Proteins, Signal Transducing / genetics*
Adaptor Proteins, Signal Transducing / metabolism
Adenosine Triphosphatases / genetics*
Adenosine Triphosphatases / metabolism
Animals
Apoptosis Regulatory Proteins
Caenorhabditis elegans
Caenorhabditis elegans Proteins / genetics*
Caenorhabditis elegans Proteins / metabolism
Carrier Proteins / genetics*
Carrier Proteins / metabolism
Cell Cycle Proteins / genetics*
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Chromatin / metabolism*
Chromosomal Proteins, Non-Histone / genetics
Chromosomal Proteins, Non-Histone / metabolism
DNA Replication / genetics*
Embryo, Nonmammalian
HEK293 Cells
Humans
Immunoprecipitation
Ligases / metabolism*
Microscopy
Time-Lapse Imaging
Valosin Containing Protein
|
| IF |
12.121
|
| 引用数 |
15
|
| リソース情報 |
| 線虫 |
tm544
tm659
tm6658
tm6659 |
