1. Academic Validation
  2. Ubiquitin-like protein UBL5 promotes the functional integrity of the Fanconi anemia pathway

Ubiquitin-like protein UBL5 promotes the functional integrity of the Fanconi anemia pathway

  • EMBO J. 2015 May 12;34(10):1385-98. doi: 10.15252/embj.201490376.
Yasuyoshi Oka 1 Simon Bekker-Jensen 2 Niels Mailand 2
Affiliations

Affiliations

  • 1 Ubiquitin Signaling Group, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 2 Ubiquitin Signaling Group, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark [email protected] [email protected].
Abstract

Ubiquitin and ubiquitin-like proteins (UBLs) function in a wide array of cellular processes. UBL5 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 UBL5 in promoting the function of the Fanconi anemia (FA) pathway for repair of DNA interstrand crosslinks (ICLs), mediated by a specific interaction with the central FA pathway component FANCI. UBL5-deficient cells display spliceosome-independent reduction of FANCI protein stability, defective FANCI function in response to DNA damage and hypersensitivity to ICLs. By mapping the sequence determinants underlying UBL5-FANCI binding, we generated separation-of-function mutants to demonstrate that key aspects of FA pathway function, including FANCI-FANCD2 heterodimerization, FANCD2 and FANCI monoubiquitylation and maintenance of chromosome stability after ICLs, are compromised when the UBL5-FANCI interaction is selectively inhibited by mutations in either protein. Together, our findings establish UBL5 as a factor that promotes the functionality of the FA DNA repair pathway.

Keywords

DNA damage response; FANCI; Fanconi anemia; UBL5; protein stability.

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