7zf1
From Proteopedia
Structure of ubiquitinated FANCI in complex with FANCD2 and double-stranded DNA
Structural highlights
DiseaseFANCI_HUMAN Fanconi anemia. The disease is caused by variants affecting the gene represented in this entry. FunctionFANCI_HUMAN Plays an essential role in the repair of DNA double-strand breaks by homologous recombination and in the repair of interstrand DNA cross-links (ICLs) by promoting FANCD2 monoubiquitination by FANCL and participating in recruitment to DNA repair sites. Required for maintenance of chromosomal stability. Specifically binds branched DNA: binds both single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA). Participates in S phase and G2 phase checkpoint activation upon DNA damage.[1] [2] [3] [4] [5] Publication Abstract from PubMedDi-monoubiquitination of the FANCI-FANCD2 (ID2) complex is a central and crucial step for the repair of DNA interstrand crosslinks via the Fanconi anaemia pathway. While FANCD2 ubiquitination precedes FANCI ubiquitination, FANCD2 is also deubiquitinated at a faster rate than FANCI, which can result in a FANCI-ubiquitinated ID2 complex (I(Ub) D2). Here, we present a 4.1 A cryo-EM structure of I(Ub) D2 complex bound to double-stranded DNA. We show that this complex, like ID2(Ub) and I(Ub) D2(Ub) , is also in the closed ID2 conformation and clamps on DNA. The target lysine of FANCD2 (K561) becomes fully exposed in the I(Ub) D2-DNA structure and is thus primed for ubiquitination. Similarly, FANCI's target lysine (K523) is also primed for ubiquitination in the ID2(Ub) -DNA complex. The I(Ub) D2-DNA complex exhibits deubiquitination resistance, conferred by the presence of DNA and FANCD2. ID2(Ub) -DNA, on the other hand, can be efficiently deubiquitinated by USP1-UAF1, unless further ubiquitination on FANCI occurs. Therefore, FANCI ubiquitination effectively maintains FANCD2 ubiquitination in two ways: it prevents excessive FANCD2 deubiquitination within an I(Ub) D2(Ub) -DNA complex, and it enables re-ubiquitination of FANCD2 within a transient, closed-on-DNA, I(Ub) D2 complex. Structural and biochemical basis of interdependent FANCI-FANCD2 ubiquitination.,Lemonidis K, Rennie ML, Arkinson C, Chaugule VK, Clarke M, Streetley J, Walden H EMBO J. 2023 Feb 1;42(3):e111898. doi: 10.15252/embj.2022111898. Epub 2022 Nov , 17. PMID:36385258[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||
