Distinct functional roles for the two SLX4 ubiquitin-binding UBZ domains mutated in Fanconi anemia

Please always quote using this URN: urn:nbn:de:bvb:20-opus-120908
  • Defects in SLX4, a scaffold for DNA repair nucleases, cause Fanconi anemia due to defective repair of inter-strand DNA crosslinks (ICLs). Some FA patients have an SLX4 deletion removing two tandem UBZ4-type ubiquitin-binding domains, implicated in protein recruitment to sites of DNA damage. Here we show that human SLX4 is recruited to sites of ICL induction but the UBZ-deleted form of SLX4 in cells from FA patients is not. SLX4 recruitment does not require ubiquitination of FANCD2, or the E3 ligases RNF8, RAD18 and BRCA1. We show that the firstDefects in SLX4, a scaffold for DNA repair nucleases, cause Fanconi anemia due to defective repair of inter-strand DNA crosslinks (ICLs). Some FA patients have an SLX4 deletion removing two tandem UBZ4-type ubiquitin-binding domains, implicated in protein recruitment to sites of DNA damage. Here we show that human SLX4 is recruited to sites of ICL induction but the UBZ-deleted form of SLX4 in cells from FA patients is not. SLX4 recruitment does not require ubiquitination of FANCD2, or the E3 ligases RNF8, RAD18 and BRCA1. We show that the first (UBZ-1), but not the second UBZ domain of SLX4 binds to ubiquitin polymers with a preference for K63-linked chains. Furthermore, UBZ-1 is required for SLX4 recruitment to ICL sites, and for efficient ICL repair in murine fibroblasts. SLX4 UBZ-2 domain does not bind ubiquitin in vitro or contribute to ICL repair, but it is required for resolution of Holliday junctions in vivo. These data shed light on SLX4 recruitment, and suggest that there remain to be identified ubiquitinated ligands and E3 ligases critical for ICL repair.show moreshow less

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Metadaten
Author: Christophe Lachaud, Dennis Castor, Karolina Hain, Ivan Muñoz, Jamie Wilson, Thomas J. MacArtney, Detlev Schindler, John Rouse
URN:urn:nbn:de:bvb:20-opus-120908
Document Type:Journal article
Faculties:Medizinische Fakultät / Institut für Humangenetik
Language:English
Parent Title (English):Journal of Cell Science
ISSN:1477-9137
Year of Completion:2014
Volume:127
Issue:13
Pagenumber:2811-7
Source:Journal of Cell Science (2014) 127, 2811–2817 doi:10.1242/jcs.146167
DOI:https://doi.org/10.1242/jcs.146167
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/24794496
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:FANCP; ICL; SLX4; UBZ; fanconi anemia; ubiquitin
Release Date:2016/02/16
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung