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.…
Author: | Christophe Lachaud, Dennis Castor, Karolina Hain, Ivan Muñoz, Jamie Wilson, Thomas J. MacArtney, Detlev Schindler, John Rouse |
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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): | CC BY: Creative-Commons-Lizenz: Namensnennung |