7zf1 | pdb_00007zf1

Structure of ubiquitinated FANCI in complex with FANCD2 and double-stranded DNA

Structural highlights

7zf1 is a 5 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 4.14Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

FANCI_HUMAN Fanconi anemia. The disease is caused by variants affecting the gene represented in this entry.

Function

FANCI_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 PubMed

Di-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

↑ Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald ER 3rd, Hurov KE, Luo J, Ballif BA, Gygi SP, Hofmann K, D'Andrea AD, Elledge SJ. Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell. 2007 Apr 20;129(2):289-301. doi: 10.1016/j.cell.2007.03.009. Epub 2007 Apr , 5. PMID:17412408 doi:https://dx.doi.org/10.1016/j.cell.2007.03.009
↑ Dorsman JC, Levitus M, Rockx D, Rooimans MA, Oostra AB, Haitjema A, Bakker ST, Steltenpool J, Schuler D, Mohan S, Schindler D, Arwert F, Pals G, Mathew CG, Waisfisz Q, de Winter JP, Joenje H. Identification of the Fanconi anemia complementation group I gene, FANCI. Cell Oncol. 2007;29(3):211-8. PMID:17452773
↑ Sims AE, Spiteri E, Sims RJ 3rd, Arita AG, Lach FP, Landers T, Wurm M, Freund M, Neveling K, Hanenberg H, Auerbach AD, Huang TT. FANCI is a second monoubiquitinated member of the Fanconi anemia pathway. Nat Struct Mol Biol. 2007 Jun;14(6):564-7. Epub 2007 Apr 25. PMID:17460694 doi:https://dx.doi.org/nsmb1252
↑ Alpi AF, Pace PE, Babu MM, Patel KJ. Mechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI. Mol Cell. 2008 Dec 26;32(6):767-77. doi: 10.1016/j.molcel.2008.12.003. PMID:19111657 doi:https://dx.doi.org/10.1016/j.molcel.2008.12.003
↑ Oka Y, Bekker-Jensen S, Mailand N. Ubiquitin-like protein UBL5 promotes the functional integrity of the Fanconi anemia pathway. EMBO J. 2015 May 12;34(10):1385-98. PMID:25862789 doi:10.15252/embj.201490376
↑ Lemonidis K, Rennie ML, Arkinson C, Chaugule VK, Clarke M, Streetley J, Walden H. Structural and biochemical basis of interdependent FANCI-FANCD2 ubiquitination. EMBO J. 2023 Feb 1;42(3):e111898. PMID:36385258 doi:10.15252/embj.2022111898

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OCA

[1] Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald ER 3rd, Hurov KE, Luo J, Ballif BA, Gygi SP, Hofmann K, D'Andrea AD, Elledge SJ. Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell. 2007 Apr 20;129(2):289-301. doi: 10.1016/j.cell.2007.03.009. Epub 2007 Apr , 5. PMID:17412408 doi:https://dx.doi.org/10.1016/j.cell.2007.03.009

[2] Dorsman JC, Levitus M, Rockx D, Rooimans MA, Oostra AB, Haitjema A, Bakker ST, Steltenpool J, Schuler D, Mohan S, Schindler D, Arwert F, Pals G, Mathew CG, Waisfisz Q, de Winter JP, Joenje H. Identification of the Fanconi anemia complementation group I gene, FANCI. Cell Oncol. 2007;29(3):211-8. PMID:17452773

[3] Sims AE, Spiteri E, Sims RJ 3rd, Arita AG, Lach FP, Landers T, Wurm M, Freund M, Neveling K, Hanenberg H, Auerbach AD, Huang TT. FANCI is a second monoubiquitinated member of the Fanconi anemia pathway. Nat Struct Mol Biol. 2007 Jun;14(6):564-7. Epub 2007 Apr 25. PMID:17460694 doi:https://dx.doi.org/nsmb1252

[4] Alpi AF, Pace PE, Babu MM, Patel KJ. Mechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI. Mol Cell. 2008 Dec 26;32(6):767-77. doi: 10.1016/j.molcel.2008.12.003. PMID:19111657 doi:https://dx.doi.org/10.1016/j.molcel.2008.12.003

[5] Oka Y, Bekker-Jensen S, Mailand N. Ubiquitin-like protein UBL5 promotes the functional integrity of the Fanconi anemia pathway. EMBO J. 2015 May 12;34(10):1385-98. PMID:25862789 doi:10.15252/embj.201490376

[6] Lemonidis K, Rennie ML, Arkinson C, Chaugule VK, Clarke M, Streetley J, Walden H. Structural and biochemical basis of interdependent FANCI-FANCD2 ubiquitination. EMBO J. 2023 Feb 1;42(3):e111898. PMID:36385258 doi:10.15252/embj.2022111898

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7zf1 | pdb_00007zf1

Structure of ubiquitinated FANCI in complex with FANCD2 and double-stranded DNA

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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