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Ubiquitin‐like protein UBL 5 promotes the functional integrity of the Fanconi anemia pathway
Author(s) -
Oka Yasuyoshi,
BekkerJensen Simon,
Mailand Niels
Publication year - 2015
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201490376
Subject(s) - library science , foundation (evidence) , biomedical sciences , ubiquitin , medicine , family medicine , biology , political science , law , genetics , pathology , computer science , gene
Ubiquitin and ubiquitin‐like proteins ( UBL s) function in a wide array of cellular processes. UBL 5 is an atypical UBL that does not form covalent conjugates with cellular proteins and which has a known role in modulating pre‐ mRNA splicing. Here, we report an unexpected involvement of human UBL 5 in promoting the function of the Fanconi anemia ( FA ) pathway for repair of DNA interstrand crosslinks ( ICL s), mediated by a specific interaction with the central FA pathway component FANCI . UBL 5‐deficient cells display spliceosome‐independent reduction of FANCI protein stability, defective FANCI function in response to DNA damage and hypersensitivity to ICL s. By mapping the sequence determinants underlying UBL 5– FANCI binding, we generated separation‐of‐function mutants to demonstrate that key aspects of FA pathway function, including FANCI – FANCD 2 heterodimerization, FANCD 2 and FANCI monoubiquitylation and maintenance of chromosome stability after ICL s, are compromised when the UBL 5– FANCI interaction is selectively inhibited by mutations in either protein. Together, our findings establish UBL 5 as a factor that promotes the functionality of the FA DNA repair pathway.