Identification of KIAA1018/FAN1, a DNA Repair Nuclease Recruited to DNA Damage by Monoubiquitinated FANCD2

Craig MacKay, Anne-Cecile Declais, Cecilia Lundin, Ana Agostinho, Andrew J. Deans, Thomas J. MacArtney, Kay Hofmann, Anton Gartner, Stephen C. West, Thomas Helleday, David M. J. Lilley, John Rouse (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    196 Citations (Scopus)

    Abstract

    DNA interstrand crosslinks (ICLs) are highly toxic because they block the progression of replisomes. The Fanconi Anemia (FA) proteins, encoded by genes that are mutated in FA, are important for repair of ICLs. The FA core complex catalyzes the monoubiquitination of FANCD2, and this event is essential for several steps of ICL repair. However, how monoubiquitination of FANCD2 promotes ICL repair at the molecular level is unknown. Here, we describe a highly conserved protein, KIAA1018/MTMR15/FAN1, that interacts with, and is recruited to sites of DNA damage by, the monoubiquitinated form of FANCD2. FAN1 exhibits endonuclease activity toward 50 flaps and has 5' exonuclease activity, and these activities are mediated by an ancient VRR_nuc domain. Depletion of FAN1 from human cells causes hypersensitivity to ICLs, defects in ICL repair, and genome instability. These data at least partly explain how ubiquitination of FANCD2 promotes DNA repair.

    Original languageEnglish
    Pages (from-to)65-76
    Number of pages12
    JournalCell
    Volume142
    Issue number1
    DOIs
    Publication statusPublished - 9 Jul 2010

    Keywords

    • CROSS-LINK REPAIR
    • HOLLIDAY JUNCTION RESOLVASE
    • DOUBLE-STRAND BREAKS
    • ANEMIA CORE COMPLEX
    • FANCONI-ANEMIA
    • MAMMALIAN-CELLS
    • PATHWAY
    • REPLICATION
    • PROTEINS
    • ACTIVATION

    Cite this

    MacKay, Craig ; Declais, Anne-Cecile ; Lundin, Cecilia ; Agostinho, Ana ; Deans, Andrew J. ; MacArtney, Thomas J. ; Hofmann, Kay ; Gartner, Anton ; West, Stephen C. ; Helleday, Thomas ; Lilley, David M. J. ; Rouse, John. / Identification of KIAA1018/FAN1, a DNA Repair Nuclease Recruited to DNA Damage by Monoubiquitinated FANCD2. In: Cell. 2010 ; Vol. 142, No. 1. pp. 65-76.
    @article{c67140cd27dc4183a89a3202638424b0,
    title = "Identification of KIAA1018/FAN1, a DNA Repair Nuclease Recruited to DNA Damage by Monoubiquitinated FANCD2",
    abstract = "DNA interstrand crosslinks (ICLs) are highly toxic because they block the progression of replisomes. The Fanconi Anemia (FA) proteins, encoded by genes that are mutated in FA, are important for repair of ICLs. The FA core complex catalyzes the monoubiquitination of FANCD2, and this event is essential for several steps of ICL repair. However, how monoubiquitination of FANCD2 promotes ICL repair at the molecular level is unknown. Here, we describe a highly conserved protein, KIAA1018/MTMR15/FAN1, that interacts with, and is recruited to sites of DNA damage by, the monoubiquitinated form of FANCD2. FAN1 exhibits endonuclease activity toward 50 flaps and has 5' exonuclease activity, and these activities are mediated by an ancient VRR_nuc domain. Depletion of FAN1 from human cells causes hypersensitivity to ICLs, defects in ICL repair, and genome instability. These data at least partly explain how ubiquitination of FANCD2 promotes DNA repair.",
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    author = "Craig MacKay and Anne-Cecile Declais and Cecilia Lundin and Ana Agostinho and Deans, {Andrew J.} and MacArtney, {Thomas J.} and Kay Hofmann and Anton Gartner and West, {Stephen C.} and Thomas Helleday and Lilley, {David M. J.} and John Rouse",
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    language = "English",
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    MacKay, C, Declais, A-C, Lundin, C, Agostinho, A, Deans, AJ, MacArtney, TJ, Hofmann, K, Gartner, A, West, SC, Helleday, T, Lilley, DMJ & Rouse, J 2010, 'Identification of KIAA1018/FAN1, a DNA Repair Nuclease Recruited to DNA Damage by Monoubiquitinated FANCD2', Cell, vol. 142, no. 1, pp. 65-76. https://doi.org/10.1016/j.cell.2010.06.021

    Identification of KIAA1018/FAN1, a DNA Repair Nuclease Recruited to DNA Damage by Monoubiquitinated FANCD2. / MacKay, Craig; Declais, Anne-Cecile; Lundin, Cecilia; Agostinho, Ana; Deans, Andrew J.; MacArtney, Thomas J.; Hofmann, Kay; Gartner, Anton; West, Stephen C.; Helleday, Thomas; Lilley, David M. J.; Rouse, John (Lead / Corresponding author).

    In: Cell, Vol. 142, No. 1, 09.07.2010, p. 65-76.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Identification of KIAA1018/FAN1, a DNA Repair Nuclease Recruited to DNA Damage by Monoubiquitinated FANCD2

    AU - MacKay, Craig

    AU - Declais, Anne-Cecile

    AU - Lundin, Cecilia

    AU - Agostinho, Ana

    AU - Deans, Andrew J.

    AU - MacArtney, Thomas J.

    AU - Hofmann, Kay

    AU - Gartner, Anton

    AU - West, Stephen C.

    AU - Helleday, Thomas

    AU - Lilley, David M. J.

    AU - Rouse, John

    PY - 2010/7/9

    Y1 - 2010/7/9

    N2 - DNA interstrand crosslinks (ICLs) are highly toxic because they block the progression of replisomes. The Fanconi Anemia (FA) proteins, encoded by genes that are mutated in FA, are important for repair of ICLs. The FA core complex catalyzes the monoubiquitination of FANCD2, and this event is essential for several steps of ICL repair. However, how monoubiquitination of FANCD2 promotes ICL repair at the molecular level is unknown. Here, we describe a highly conserved protein, KIAA1018/MTMR15/FAN1, that interacts with, and is recruited to sites of DNA damage by, the monoubiquitinated form of FANCD2. FAN1 exhibits endonuclease activity toward 50 flaps and has 5' exonuclease activity, and these activities are mediated by an ancient VRR_nuc domain. Depletion of FAN1 from human cells causes hypersensitivity to ICLs, defects in ICL repair, and genome instability. These data at least partly explain how ubiquitination of FANCD2 promotes DNA repair.

    AB - DNA interstrand crosslinks (ICLs) are highly toxic because they block the progression of replisomes. The Fanconi Anemia (FA) proteins, encoded by genes that are mutated in FA, are important for repair of ICLs. The FA core complex catalyzes the monoubiquitination of FANCD2, and this event is essential for several steps of ICL repair. However, how monoubiquitination of FANCD2 promotes ICL repair at the molecular level is unknown. Here, we describe a highly conserved protein, KIAA1018/MTMR15/FAN1, that interacts with, and is recruited to sites of DNA damage by, the monoubiquitinated form of FANCD2. FAN1 exhibits endonuclease activity toward 50 flaps and has 5' exonuclease activity, and these activities are mediated by an ancient VRR_nuc domain. Depletion of FAN1 from human cells causes hypersensitivity to ICLs, defects in ICL repair, and genome instability. These data at least partly explain how ubiquitination of FANCD2 promotes DNA repair.

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    KW - HOLLIDAY JUNCTION RESOLVASE

    KW - DOUBLE-STRAND BREAKS

    KW - ANEMIA CORE COMPLEX

    KW - FANCONI-ANEMIA

    KW - MAMMALIAN-CELLS

    KW - PATHWAY

    KW - REPLICATION

    KW - PROTEINS

    KW - ACTIVATION

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