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

被引：262

作者：

MacKay, Craig ^{[1
,2
]}

Declais, Anne-Cecile

Lundin, Cecilia ^{[4
]}

Agostinho, Ana ^{[3
]}

Deans, Andrew J. ^{[6
]}

MacArtney, Thomas J. ^{[1
]}

Hofmann, Kay ^{[5
]}

Gartner, Anton ^{[3
]}

West, Stephen C. ^{[6
]}

Helleday, Thomas ^{[4
,7
]}

Lilley, David M. J. ^{[2
]}

Rouse, John ^{[1
]}

机构：

[1] Univ Dundee, Coll Life Sci, MRC, Prot Phosphorylat Unit, Dundee DD1 5EH, Scotland

[2] Univ Dundee, Coll Life Sci, CRUK Nucle Acids Struct Res Grp, Dundee DD1 5EH, Scotland

[3] Univ Dundee, Coll Life Sci, Wellcome Trust Ctr Gene Regulat & Express, Dundee DD1 5EH, Scotland

[4] Univ Oxford, Gray Inst Radiat Oncol & Biol, Oxford OX3 7DQ, England

[5] Miltenyi Biotec GmbH, D-51429 Bergisch Gladbach, Germany

[6] Canc Res UK, London Res Inst, Clare Hall Labs, S Mimms EN6 3LD, Herts, England

[7] Stockholm Univ, Dept Genet Microbiol & Toxicol, S-10691 Stockholm, Sweden

来源：

CELL | 2010年 / 142卷 / 01期

基金：

英国生物技术与生命科学研究理事会; 英国医学研究理事会;

关键词：

HOLLIDAY JUNCTION RESOLVASE; FANCONI-ANEMIA; CROSS-LINKS; REPLICATION; PROTEIN; ACTIVATION; KINETICS; DOMAINS; FAAP24; BRCA1;

D O I：

10.1016/j.cell.2010.06.021

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：65 / 76

页数：12

共 32 条

[1]

DNA replication is required to elicit cellular responses to psoralen-induced DNA interstrand cross-links [J].