Franz, Andre, Pirson, Paul A., Pilger, Domenic ORCID: 0000-0001-7339-0685, Halder, Swagata, Achuthankutty, Divya, Kashkar, Hamid, Ramadan, Kristijan and Hoppe, Thorsten ORCID: 0000-0002-4734-9352 (2016). Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard DNA replication fork progression. Nat. Commun., 7. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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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 chromatinassociated protein degradation in both Caenorhabditis elegans and humans, which is relevant to oncogenesis and aging.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Franz, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pirson, Paul A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pilger, DomenicUNSPECIFIEDorcid.org/0000-0001-7339-0685UNSPECIFIED
Halder, SwagataUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Achuthankutty, DivyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kashkar, HamidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramadan, KristijanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoppe, ThorstenUNSPECIFIEDorcid.org/0000-0002-4734-9352UNSPECIFIED
URN: urn:nbn:de:hbz:38-285262
DOI: 10.1038/ncomms10612
Journal or Publication Title: Nat. Commun.
Volume: 7
Date: 2016
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CAENORHABDITIS-ELEGANS EMBRYOS; AAA-ATPASE; CELL-CYCLE; S-PHASE; CHROMOSOMAL INSTABILITY; PROTEIN-DEGRADATION; GENOMIC INSTABILITY; MCM2-7 HELICASE; COMPLEX; DAMAGEMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/28526

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