Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard DNA replication fork progression

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 tha...

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Published in:Nature communications Vol. 7; no. 1; pp. 10612 - 15
Main Authors: Franz, André, Pirson, Paul A., Pilger, Domenic, Halder, Swagata, Achuthankutty, Divya, Kashkar, Hamid, Ramadan, Kristijan, Hoppe, Thorsten
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 04.02.2016
Nature Publishing Group
Nature Portfolio
Subjects:
13/1
13/106
13/51
13/89
14/19
14/34
14/35
38/70
631/337/100
631/337/474
631/337/641/151
64/11
82/80
82/83
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Adenosine Triphosphatases - genetics
Adenosine Triphosphatases - metabolism
Animals
Apoptosis Regulatory Proteins
Biodegradation
Caenorhabditis elegans
Caenorhabditis elegans Proteins - genetics
Caenorhabditis elegans Proteins - metabolism
Cancer
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell division
Cell Line, Tumor
Chromatin - metabolism
Chromosomal Proteins, Non-Histone - genetics
Chromosomal Proteins, Non-Histone - metabolism
Deoxyribonucleic acid
DNA
DNA Replication - genetics
Embryo, Nonmammalian
Genomes
HEK293 Cells
Humanities and Social Sciences
Humans
Immunoprecipitation
Inactivation
Licenses
Ligases - metabolism
Medical research
Metabolism
Microscopy
multidisciplinary
Nematodes
Oncology
Proteins
Science
Science (multidisciplinary)
Time-Lapse Imaging
Valosin Containing Protein
Yeast
Germany
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary: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. Cdc48/p97 is a key component of the ubiquitin-proteasome system, acting as a ubiquitin-directed segregase to regulate multiple cellular functions. Here the authors identify UBXN-3/FAF1 as a crucial regulator of chromatin-associated protein degradation that recruits Cdc48/p97 to DNA replication forks.
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ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms10612