A Genetic Screen Identifies FAN1, a Fanconi Anemia-Associated Nuclease Necessary for DNA Interstrand Crosslink Repair

被引：271

作者：

Smogorzewska, Agata ^{[1
,2
,3
]}

Desetty, Rohini ^{[3
]}

Saito, Takamune T.

Schlabach, Michael ^{[1
]}

Lach, Francis P. ^{[3
]}

Sowa, Mathew E. ^{[4
]}

Clark, Alan B. ^{[5
,6
]}

Kunkel, Thomas A. ^{[5
,6
]}

Harper, J. Wade ^{[4
]}

Colaiacovo, Monica P.

Elledge, Stephen J. ^{[1
]}

机构：

[1] Harvard Univ, Sch Med,Brigham & Womens Hosp, Howard Hughes Med Inst, Dept Genet,Dept Med,Div Genet, Boston, MA 02115 USA

[2] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[3] Rockefeller Univ, Lab Genome Maintenance, New York, NY 10065 USA

[4] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

[5] NIEHS, Genet Mol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA

[6] NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA

来源：

MOLECULAR CELL | 2010年 / 39卷 / 01期

基金：

美国国家卫生研究院;

关键词：

HOLLIDAY JUNCTION RESOLVASE; DAMAGE; CANCER; FANCD2; SUSCEPTIBILITY; RECOMBINATION; PROTEIN; PHOSPHORYLATION; MECHANISM; SUBUNIT;

D O I：

10.1016/j.molcel.2010.06.023

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The Fanconi anemia (FA) pathway is responsible for interstrand crosslink repair. At the heart of this pathway is the FANCI-FAND2 (ID) complex, which, upon ubiquitination by the FA core complex, travels to sites of damage to coordinate repair that includes nucleolytic modification of the DNA surrounding the lesion and translesion synthesis. How the ID complex regulates these events is unknown. Here we describe a shRNA screen that led to the identification of two nucleases necessary for crosslink repair, FAN1 (KIAA1018) and EXDL2. FAN1 colocalizes at sites of DNA damage with the ID complex in a manner dependent on FAN1's ubiquitin-binding domain (UBZ), the ID complex, and monoubiquitination of FANCD2. FAN1 possesses intrinsic 5'-3' exonuclease activity and endonuclease activity that cleaves nicked and branched structures. We propose that FAN1 is a repair nuclease that is recruited to sites of crosslink damage in part through binding the ubiquitinated ID complex through its UBZ domain.

引用

页码：36 / 47

页数：12

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