The FA Core Complex Contains a Homo-dimeric Catalytic Module for the Symmetric Mono-ubiquitination of FANCI-FANCD2

Swuec, Paolo; Renault, Ludovic; Borg, Annabel; Shah, Fenil; Murphy, Vincent J.; Twest, Sylvie van; Snijders, Ambrosius P.; Deans, Andrew J.; Costa, Alessandro

doi:10.1016/j.celrep.2016.11.013

Cited by 55 publications

(64 citation statements)

References 52 publications

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“…FANCD2 ubiquitination was found to modulate ID2-dsDNA binding affinity, whereas FANCI ubiquitination was found to largely protect the ubiquitinated ID2 complex from deubiquitination. A simple explanation for our data is that the ID2 complex can explore two different conformational extremes: an open state, as in the previously reported non-ubiquitinated ID2 crystal structure and EM maps [12,18,32], and a closed state, as observed here ( Figure 5). We propose that DNA binding allows ID2 to reach the closed ID2 conformation, in which the Arm ID2 interface forms.…”

Section: Discussionsupporting

confidence: 78%

“…Reference-free 2D class averages of ID2 Ub and I Ub D2 Ub -dsDNA exhibited similar overall shapes, but different to previous non-ubiquitinated ID2 class averages [12], hinting at a gross conformational change upon ubiquitination of FANCD2. Reconstructed maps of ID2 Ub and I Ub D2 Ub -dsDNA, at resolutions of 25 and 12 Å, respectively, both exhibited a closed, torus-like shape.…”

Section: Ubiquitination Of Fancd2 Is Associated With Formation Of a Scontrasting

confidence: 56%

“…Ube2T-FANCL are the E2-E3 pair that mediate ubiquitination [10,11]. In many eukaryotes, including humans, FANCL is incorporated into a pseudodimeric ~1 MDa complex which is known as the FA core complex [12][13][14]. Removal of the ubiquitins, on FANCI and FANCD2, is also critical for the FA pathway, and this deubiquitination step is catalysed by the USP1-UAF1 complex [15,16].…”

Section: Introductionmentioning

confidence: 99%

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Differential functions of FANCI and FANCD2 ubiquitination stabilize ID2 complex on DNA

Rennie

Lemonidis

Arkinson

et al. 2020

Preprint

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The Fanconi Anemia (FA) pathway is a dedicated pathway for the repair of DNA interstrand crosslinks, and which is additionally activated in response to other forms of replication stress. A key step in the activation of the FA pathway is the monoubiquitination of each of the two subunits (FANCI and FANCD2) of the ID2 complex on specific lysine residues. However, the molecular function of these modifications has been unknown for nearly two decades. Here we find that ubiquitination of FANCD2 acts to increase ID2's affinity for double stranded DNA via promoting/stabilizing a large-scale conformational change in the complex, resulting in a secondary "Arm" ID2 interphase encircling DNA. Ubiquitination of FANCI, on the other hand, largely protects the ubiquitin on FANCD2 from USP1/UAF deubiquitination, with key hydrophobic residues of FANCI's ubiquitin being important for this protection. In effect, both of these post-translational modifications function to stabilise a conformation in which the ID2 complex encircles DNA.

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Section: Discussionsupporting

confidence: 78%

Section: Ubiquitination Of Fancd2 Is Associated With Formation Of a Scontrasting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Differential functions of FANCI and FANCD2 ubiquitination stabilize ID2 complex on DNA

Rennie

Lemonidis

Arkinson

et al. 2020

Preprint

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“…The data collected at eBIC have, at the time of writing, generated ten research publications (Hospenthal et al, 2016;Serna et al, 2016;Joseph et al, 2016;Wilkinson et al, 2016;Iadanza et al, 2016;Ramsay et al, 2016;Fica et al, 2017;Swuec et al, 2017;Ilangovan et al, 2017;Boland et al, 2017). We have also received a number of personal communications from inhouse and external users reporting reconstructions at better than 4 Å resolution, with a few extending beyond 3 Å .…”

Section: Results From the First Year Of Ebicmentioning

confidence: 99%

Electron Bio-Imaging Centre (eBIC): the UK national research facility for biological electron microscopy

Clare

Siebert

Hecksel

et al. 2017

Acta Cryst Sect D Struct Biol

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The recent resolution revolution in cryo-EM has led to a massive increase in demand for both time on high-end cryo-electron microscopes and access to cryoelectron microscopy expertise. In anticipation of this demand, eBIC was set up at Diamond Light Source in collaboration with Birkbeck College London and the University of Oxford, and funded by the Wellcome Trust, the UK Medical Research Council (MRC) and the Biotechnology and Biological Sciences Research Council (BBSRC) to provide access to high-end equipment through peer review. eBIC is currently in its start-up phase and began by offering time on a single FEI Titan Krios microscope equipped with the latest generation of direct electron detectors from two manufacturers. Here, the current status and modes of access for potential users of eBIC are outlined. In the first year of operation, 222 d of microscope time were delivered to external research groups, with 95 visits in total, of which 53 were from unique groups. The data collected have generated multiple high-to intermediate-resolution structures (2.8-8 Å ), ten of which have been published. A second Krios microscope is now in operation, with two more due to come online in 2017. In the next phase of growth of eBIC, in addition to more microscope time, new data-collection strategies and sample-preparation techniques will be made available to external user groups. Finally, all raw data are archived, and a metadata catalogue and automated pipelines for data analysis are being developed.

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“…Yet, increasing FANCD2 monoubiquitination by inhibiting USP1, the de-ubiquitinating enzyme for FANCD2, is unlikely to restore the function of the FA pathway [17, 18]. Recent studies have focused on the basic biochemistry of the FANCD2 monoubiquitination reaction [40, 41]. In vitro studies such as these may provide critical information for the design of small molecules that can restore monoubiquitination in a manner that is therapeutically effective [42].…”

Section: New Genesmentioning

confidence: 99%

Recent insights into the molecular basis of Fanconi anemia: genes, modifiers, and drivers

Cheung

Taniguchi

2017

Int J Hematol

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Fanconi anemia (FA), the most common form of inherited bone marrow failure, predisposes to leukemia and solid tumors. FA is caused by the genetic disruption of a cellular pathway that repairs DNA interstrand crosslinks. The impaired function of this pathway, and the genetic instability that results, is considered the main pathogenic mechanism behind this disease. The identification of breast cancer susceptibility genes (for example, BRCA1/FANCS and BRCA2/FANCD1) as being major players in the FA pathway has led to a surge in molecular studies, resulting in the concept of the FA-BRCA pathway. In this review, we discuss recent advances in the molecular pathogenesis of FA from three viewpoints: i) new FA genes, ii) modifier pathways that influence the cellular and clinical phenotypes of FA and iii) non-canonical functions of FA genes that may drive disease progression independently of deficient DNA repair. Potential therapeutic approaches for FA that are relevant to each will also be proposed.

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The FA Core Complex Contains a Homo-dimeric Catalytic Module for the Symmetric Mono-ubiquitination of FANCI-FANCD2

Cited by 55 publications

References 52 publications

Differential functions of FANCI and FANCD2 ubiquitination stabilize ID2 complex on DNA

Differential functions of FANCI and FANCD2 ubiquitination stabilize ID2 complex on DNA

Electron Bio-Imaging Centre (eBIC): the UK national research facility for biological electron microscopy

Recent insights into the molecular basis of Fanconi anemia: genes, modifiers, and drivers

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