Identification of the Fanconi Anemia Complementation Group I Gene, <i>FANCI</i>

Dorsman, Josephine C.; Levitus, Marieke; Rockx, Davy; Rooimans, Martin A.; Oostra, Anneke B.; Haitjema, Anneke; Bakker, Sietske T.; Steltenpool, Jûrgen; Schüler, D.; Mohan, Sheila; Schindler, Detlev; Arwert, Fré; Pals, Gerard; Mathew, Christopher; Waisfisz, Quinten; Winter, Johan P. de; Joenje, Hans

doi:10.1155/2007/151968

Cited by 51 publications

(42 citation statements)

References 15 publications

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“…Curiously however, the ubiquitination of FANCI remains inefficient and delayed when compared to FANCD2 modification, as clearly visualized in a time course experiment (Figure 6 ). Since in cells, both FANCD2 and FANCI are ubiquitinated in response to DNA damage ( 12 – 14 ), we examined whether the monoubiquitination of purified FANCI alone is also stimulated by the presence of DNA. Importantly, the addition of various forms of DNA greatly enhanced FANCI monoubiquitination in the absence of FANCD2 (Figure 6A , lanes 11 and 12, and Figure 7 ).…”

Section: Resultsmentioning

confidence: 99%

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Regulation of FANCD2 and FANCI monoubiquitination by their interaction and by DNA

Longerich

Kwon

Tsai

et al. 2014

Nucleic Acids Research

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FANCD2 and FANCI function together in the Fanconi anemia network of deoxyribonucleic acid (DNA) crosslink repair. These proteins form the dimeric ID2 complex that binds DNA and becomes monoubiquitinated upon exposure of cells to DNA crosslinking agents. The monoubiquitinated ID2 complex is thought to facilitate DNA repair via recruitment of specific nucleases, translesion DNA polymerases and the homologous recombination machinery. Using the ubiquitin conjugating enzyme (E2) UBE2T and ubiquitin ligase (E3) FANCL, monoubiquitination of human FANCD2 and FANCI was examined. The ID2 complex is a poor substrate for monoubiquitination, consistent with the published crystal structure showing the solvent inaccessibility of the target lysines. Importantly, FANCD2 monoubiquitination within the ID2 complex is strongly stimulated by duplex or branched DNA, but unstructured single-stranded DNA or chromatinized DNA is ineffective. Interaction of FANCL with the ID2 complex is indispensable for its E3 ligase efficacy. Interestingly, mutations in FANCI that impair its DNA binding activity compromise DNA-stimulated FANCD2 monoubiquitination. Moreover, we demonstrate that in the absence of FANCD2, DNA also stimulates FANCI monoubiquitination, but in a FANCL-independent manner. These results implicate the role of a proper DNA ligand in FANCD2 and FANCI monoubiquitination, and reveal regulatory mechanisms that are dependent on protein–protein and protein–DNA interactions.

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Section: Resultsmentioning

confidence: 99%

“…FANCI is structurally related to FANCD2 ( 10 ) and, like FANCD2, is monoubiquitinated (on lysine 523) in response to DNA damage. Monoubiquitinated FANCI localizes to DNA damage foci and is required for the cellular resistance to DNA crosslinking agents ( 12 – 14 ).…”

Section: Introductionmentioning

confidence: 99%

Regulation of FANCD2 and FANCI monoubiquitination by their interaction and by DNA

Longerich

Kwon

Tsai

et al. 2014

Nucleic Acids Research

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“…FEN1 interacts with >30 proteins and plays pivotal roles in several DNA metabolic pathways including maturation of Okazaki fragments, rescue of stalled replication forks, long-patch base excision repair, nucleotide excision repair, non-homologous end-joining, resolution of di- and tri-nucleotide structures, and apoptotic DNA fragmentation [ 6 , 7 , 11 – 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…The 5’ flap structure is then recognized and incised by the structure-specific flap endonuclease FEN1 to ensure the integrity of DNA replication [ 1 – 10 ]. Additionally, FEN1 has 5’ to 3’ exonuclease activity and gap-dependent endonuclease activity that are important during maturation of Okazaki fragments and the rescue of stalled replication forks [ 6 , 11 – 16 ]. FEN1 is also involved in long-patch base excision repair, nucleotide excision repair, non-homologous end-joining, and resolution of di- and tri-nucleotide repeat secondary structures [ 7 , 17 – 19 ].…”

Section: Introductionmentioning

confidence: 99%

Human Fanconi Anemia Complementation Group A Protein Stimulates the 5’ Flap Endonuclease Activity of FEN1

et al. 2013

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In eukaryotic cells, Flap endonuclease 1 (FEN1) is a major structure-specific endonuclease that processes 5’ flapped structures during maturation of lagging strand DNA synthesis, long patch base excision repair, and rescue of stalled replication forks. Here we report that fanconi anemia complementation group A protein (FANCA), a protein that recognizes 5’ flap structures and is involved in DNA repair and maintenance of replication forks, constantly stimulates FEN1-mediated incision of both DNA and RNA flaps. Kinetic analyses indicate that FANCA stimulates FEN1 by increasing the turnover rate of FEN1 and altering its substrate affinity. More importantly, six pathogenic FANCA mutants are significantly less efficient than the wild-type at stimulating FEN1 endonuclease activity, implicating that regulation of FEN1 by FANCA contributes to the maintenance of genomic stability.

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“…FANCI is the most recently identified FA gene ( 11 – 13 ). FANCI protein is believed to form a FANCI-FANCD2 (ID) complex with FANCD2, because they co-immunoprecipitate with each other from cell lysates and their stabilities are interdependent of each other ( 9 , 11 , 13 ).…”

mentioning

confidence: 99%

FANCI Protein Binds to DNA and Interacts with FANCD2 to Recognize Branched Structures

Yuan¹,

Hokayem²,

Zhou³

et al. 2009

Journal of Biological Chemistry

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In this study, we report that the purified wild-type FANCI (Fanconi anemia complementation group I) protein directly binds to a variety of DNA substrates. The DNA binding domain roughly encompasses residues 200–1000, as suggested by the truncation study. When co-expressed in insect cells, a small fraction of FANCI forms a stable complex with FANCD2 (Fanconi anemia complementation group D2). Intriguingly, the purified FANCI-FANCD2 complex preferentially binds to the branched DNA structures when compared with either FANCI or FANCD2 alone. Co-immunoprecipitation with purified proteins indicates that FANCI interacts with FANCD2 through its C-terminal amino acid 1001–1328 fragment. Although the C terminus of FANCI is dispensable for direct DNA binding, it seems to be involved in the regulation of DNA binding activity. This notion is further enhanced by two C-terminal point mutations, R1285Q and D1301A, which showed differentiated DNA binding activity. We also demonstrate that FANCI forms discrete nuclear foci in HeLa cells in the absence or presence of exogenous DNA damage. The FANCI foci are colocalized perfectly with FANCD2 and partially with proliferating cell nuclear antigen irrespective of mitomycin C treatment. An increased number of FANCI foci form and become resistant to Triton X extraction in response to mitomycin C treatment. Our data suggest that the FANCI-FANCD2 complex may participate in repair of damaged replication forks through its preferential recognition of branched structures.

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Identification of the Fanconi Anemia Complementation Group I Gene, FANCI

Cited by 51 publications

References 15 publications

Regulation of FANCD2 and FANCI monoubiquitination by their interaction and by DNA

Regulation of FANCD2 and FANCI monoubiquitination by their interaction and by DNA

Human Fanconi Anemia Complementation Group A Protein Stimulates the 5’ Flap Endonuclease Activity of FEN1

FANCI Protein Binds to DNA and Interacts with FANCD2 to Recognize Branched Structures

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