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

doi:10.1016/j.cell.2010.06.021

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 journal › Article › peer-review

249 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 language	English
Pages (from-to)	65-76
Number of pages	12
Journal	Cell
Volume	142
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2010.06.021
Publication status	Published - 9 Jul 2010

Keywords

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

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10.1016/j.cell.2010.06.021

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@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.",

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

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",

year = "2010",

month = jul,

day = "9",

doi = "10.1016/j.cell.2010.06.021",

language = "English",

volume = "142",

pages = "65--76",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier",

number = "1",

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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.

KW - CROSS-LINK REPAIR

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

UR - http://www.scopus.com/inward/record.url?scp=77954274685&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2010.06.021

DO - 10.1016/j.cell.2010.06.021

M3 - Article

C2 - 20603015

SN - 0092-8674

VL - 142

SP - 65

EP - 76

JO - Cell

JF - Cell

IS - 1

ER -

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

Abstract

Keywords

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Combined Genetic and Biochemical Approaches to Uncover and Characterize Redundant Factors Involved in Late Stages of Recombinational Repair

Aref#d: 19770. Division of Gene Regulation and Expression Strategic Award

Cite this

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

Abstract

Keywords

Access to Document

Other files and links

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Projects

Combined Genetic and Biochemical Approaches to Uncover and Characterize Redundant Factors Involved in Late Stages of Recombinational Repair

Aref#d: 19770. Division of Gene Regulation and Expression Strategic Award

Cite this