Mechanism, specificity and function of FANCD2‐FANCI ubiquitination and deubiquitination
| Autor: | Helen Walden, Connor Arkinson, Martin L. Rennie, Kimon Lemonidis |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities DNA Repair DNA repair Biochemistry Ubiquitin hemic and lymphatic diseases Monoubiquitination Humans FANCL Molecular Biology DNA clamp biology Chemistry Fanconi Anemia Complementation Group D2 Protein Ubiquitination nutritional and metabolic diseases Cell Biology UBA1 DNA Fanconi Anemia Complementation Group Proteins Ubiquitin ligase Cell biology Fanconi Anemia Ubiquitin-Conjugating Enzymes biology.protein Deubiquitination |
| Zdroj: | The FEBS Journal |
| ISSN: | 1742-464X |
| Popis: | Fanconi anemia (FA) is a rare genetic disorder caused by mutations in any of the currently 22 known FA genes. The products of these genes, along with other FA-associated proteins, participate in a biochemical pathway, known as the FA pathway. This pathway is responsible for the repair of DNA interstrand cross-links (ICL) and the maintenance of genomic stability in response to replication stress. At the center of the pathway is the monoubiquitination of two FA proteins, FANCD2 and FANCI, on two specific lysine residues. This is achieved by the combined action of the UBE2T ubiquitin-conjugating enzyme and a large multicomponent E3 ligase, known as the FA-core complex. This E2-E3 pair specifically targets the FANCI-FANCD2 heterodimer (ID2 complex) for ubiquitination on DNA. Deubiquitination of both FANCD2 and FANCI, which is also critical for ICL repair, is achieved by the USP1-UAF1 complex. Recent work suggests that FANCD2 ubiquitination transforms the ID2 complex into a sliding DNA clamp. Further, ID2 ubiquitination on FANCI does not alter the closed ID2 conformation observed upon FANCD2 ubiquitination and the associated ID2Ub complex with high DNA affinity. However, the resulting dimonoubiquitinated complex is highly resistant to USP1-UAF1 deubiquitination. This review will provide an update on recent work focusing on how specificity in FANCD2 ubiquitination and deubiquitination is achieved. Recent findings shedding light to the mechanisms, molecular functions, and biological roles of FANCI/FANCD2 ubiquitination and deubiquitination will be also discussed. ENZYMES: UBA1 (6.2.1.45), UBE2T (2.3.2.23), FANCL (2.3.2.27), USP1 (3.4.19.12). |
| Databáze: | OpenAIRE |
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