Identification of the FANCI protein, a monoUbiquitinated FANCD2 paralog required for DNA repair

Department of Genetics, Howard Hughes Medical Institute, Center for Genetics and Genomics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Cell (Impact Factor: 32.24). 05/2007; 129(2):289-301. DOI: 10.1016/j.cell.2007.03.009
Source: PubMed


Fanconi anemia (FA) is a developmental and cancer-predisposition syndrome caused by mutations in genes controlling DNA interstrand crosslink repair. Several FA proteins form a ubiquitin ligase that controls monoubiquitination of the FANCD2 protein in an ATR-dependent manner. Here we describe the FA protein FANCI, identified as an ATM/ATR kinase substrate required for resistance to mitomycin C. FANCI shares sequence similarity with FANCD2, likely evolving from a common ancestral gene. The FANCI protein associates with FANCD2 and, together, as the FANCI-FANCD2 (ID) complex, localize to chromatin in response to DNA damage. Like FANCD2, FANCI is monoubiquitinated and unexpectedly, ubiquitination of each protein is important for the maintenance of ubiquitin on the other, indicating the existence of a dual ubiquitin-locking mechanism required for ID complex function. Mutation in FANCI is responsible for loss of a functional FA pathway in a patient with Fanconi anemia complementation group I.

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Available from: Agata Smogorzewska, Mar 16, 2015
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    • "The activation of the FA pathway has been well revealed by the findings that K561 of FANCD2 and K523 of FANCI are monoubiquitinated by the FA complex E3 ubiquitin ligase to form a heterodimer252627 , which aggregate with the downstream proteins in nuclear foci to exert DNA crosslink and/or double DNA strand break (DSB) repair [28] . The current studies mainly focus on elucidating the modulation of FANCD2 monoubiquitination/ activation. "
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    ABSTRACT: Fanconi anemia (FA) is a rare human genetic disease, resulting from dysfunction in any of 17 known complementation proteins: FANC-A, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q & S, and other unknowns. Besides the severe bone marrow failure, an extremely high incidence of cancer as well as many other clinic symptoms associated with FA patients, FA cells are known of insufficiency in homologous recombination, DNA mismatch repair, nucleotide excision repair, translesion DNA synthesis, and other molecular defects, leading to genome instability. Those similar molecular and cellular/tissue features show that all FA proteins function in one common signaling pathway, namely, the FA pathway. The monoubiquitination of FANCD2 is the central step of the FA pathway activation upon DNA damage or during DNA replication. The molecular functions of FANCD2 emerge as a very attractive filed of investigation in cancer research. Herein, we review the recent progresses in FANCD2 functions at these rapidly progressed aspects.
    Full-text · Article · Dec 2015
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    • "The 18 genes mutated in FA patients encode proteins implicated in a common pathway that coordinates multiple repair processes and checkpoint signaling events necessary for the accurate removal of ICL lesions (Bogliolo et al., 2013; Hira et al., 2015; Kashiyama et al., 2013; Kottemann and Smogorzewska, 2013; Rickman et al., 2015; Sawyer et al., 2015; Wang and Smogorzewska , 2015). ICL repair occurs predominantly during the S-phase following replication fork stalling at the ICL that triggers monoubiquitination of FANCD2 and FANCI, the central event of the FA pathway (Akkari et al., 2000; Garcia-Higuera et al., 2001; Knipscheer et al., 2009; Smogorzewska et al., 2007). Incisions around the lesion allow unhooking of ICLs from one of the two strands and result in DNA strand breaks at the fork (Klein Douwel et al., 2014; Rä schle et al., 2008; reviewed in Sengerová et al., 2011; Zhang and Walter, 2014). "
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    ABSTRACT: Repair of DNA interstrand crosslinks requires action of multiple DNA repair pathways, including homologous recombination. Here, we report a de novo heterozygous T131P mutation in RAD51/FANCR, the key recombinase essential for homologous recombination, in a patient with Fanconi anemia-like phenotype. In vitro, RAD51-T131P displays DNA-independent ATPase activity, no DNA pairing capacity, and a co-dominant-negative effect on RAD51 recombinase function. However, the patient cells are homologous recombination proficient due to the low ratio of mutant to wild-type RAD51 in cells. Instead, patient cells are sensitive to crosslinking agents and display hyperphosphorylation of Replication Protein A due to increased activity of DNA2 and WRN at the DNA interstrand crosslinks. Thus, proper RAD51 function is important during DNA interstrand crosslink repair outside of homologous recombination. Our study provides a molecular basis for how RAD51 and its associated factors may operate in a homologous recombination-independent manner to maintain genomic integrity. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Molecular cell
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    • "Please cite this article in press as: Rickman et al., Deficiency of UBE2T, the E2 Ubiquitin Ligase Necessary for FANCD2 and FANCI Ubiquitination, Causes FA-T Subtype of Fanconi Anemia, Cell Reports (2015), described to interact with FANCL and ubiquitinate FANCD2 in vitro, but the physiological importance of this interaction has not been explored in mammalian cells (Alpi et al., 2008; Rajendra et al., 2014; Zhang et al., 2011). Activated FANCD2 and FANCI form the ID2 complex that localizes to chromatin and is required for coordinating repair at the crosslink (Garcia-Higuera et al., 2001; Knipscheer et al., 2009; Smogorzewska et al., 2007). Processing of the ICL encompasses nucleolytic unhooking of the crosslink that is dependent on FANCP/SLX4 and ERCC4/FANCQ/XPF, translesion synthesis bypass of the unhooked ICL on one strand, and double-strand break (DSB) repair by homologous recombination (HR) on the other strand (Kim et al., 2011, 2013; Klein Douwel et al., 2014; Long et al., 2011; Niedernhofer et al., 2004; Tischkowitz et al., 2007; Xia et al., 2007). "
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    ABSTRACT: Fanconi anemia (FA) is a rare bone marrow failure and cancer predisposition syndrome resulting from pathogenic mutations in genes encoding proteins participating in the repair of DNA interstrand crosslinks (ICLs). Mutations in 17 genes (FANCA-FANCS) have been identified in FA patients, defining 17 complementation groups. Here, we describe an individual presenting with typical FA features who is deficient for the ubiquitin-conjugating enzyme (E2), UBE2T. UBE2T is known to interact with FANCL, the E3 ubiquitin-ligase component of the multiprotein FA core complex, and is necessary for the monoubiquitination of FANCD2 and FANCI. Proband fibroblasts do not display FANCD2 and FANCI monoubiquitination, do not form FANCD2 foci following treatment with mitomycin C, and are hypersensitive to crosslinking agents. These cellular defects are complemented by expression of wild-type UBE2T, demonstrating that deficiency of the protein UBE2T can lead to Fanconi anemia. UBE2T gene gains an alias of FANCT. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Jun 2015 · Cell Reports
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