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PROTEIN UBIQUITYLATION

Rewiring E2 enzymes

Nature Chemical Biology volume 16, pages 227–229 (2020)Cite this article

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The site-specific monoubiquitination of FANCD2 is crucial for the Fanconi anemia DNA repair pathway and tumor suppression. This modification is mediated by the E2 enzyme UBE2T and the E3 ligase FANCL through a novel allosteric mechanism.

Several DNA repair pathways are controlled by ubiquitination, a post-translational modification with the small protein ubiquitin. Ubiquitin conjugation is achieved by the relay of ubiquitin from an activating enzyme (E1) to a conjugating enzyme (E2), and with the help of a ligase enzyme (E3), to a lysine on the target protein1. The Fanconi anemia (FA) DNA repair pathway is regulated by ubiquitination and repairs DNA interstrand crosslinks (ICLs), detrimental DNA lesions that covalently crosslink the Watson and Crick strands2. The FA pathway comprises at least 22 proteins conserved among vertebrates, and mutations in one of these factors causes the genetic disease Fanconi anemia, characterized by a high incidence of bone marrow failure and a predisposition to tumors2. A central event in this pathway is the site-specific monoubiquitination of FANCD2, which initiates ICL processing3. Although UBE2T and FANCL have been identified as the respective E2 and E3 enzymes for this modification, how they accomplish this remains unclear. In this issue of Nature Chemical Biology, Chaugule et al.4 reveal a novel allosteric mechanism by which FANCL activates UBE2T for ubiquitin transfer to FANCD2. The authors further show that a similar mechanism is used by other E2s, providing new insights into site-specific ubiquitination.

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Fig. 1: Modes of site-specific ubiquitination.

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  1. Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, the Netherlands

    Koichi Sato & Puck Knipscheer

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  1. Koichi Sato
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  2. Puck Knipscheer
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Correspondence to Koichi Sato.

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The authors declare no competing interests.

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Sato, K., Knipscheer, P. Rewiring E2 enzymes. Nat Chem Biol 16, 227–229 (2020). https://doi.org/10.1038/s41589-019-0454-8

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  • DOI: https://doi.org/10.1038/s41589-019-0454-8

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