FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway

被引：186

作者：

Ishiai, Masamichi ^{[1
]}

Kitao, Hiroyuki ^{[1
,2
]}

Smogorzewska, Agata ^{[3
,4
]}

Tomida, Junya ^{[1
]}

Kinomura, Aiko ^{[2
]}

Uchida, Emi ^{[1
]}

Saberi, Alihossein ^{[1
]}

Kinoshita, Eiji ^{[5
]}

Kinoshita-Kikuta, Emiko ^{[5
]}

Koike, Tohru ^{[5
]}

Tashiro, Satoshi ^{[6
]}

Elledge, Stephen J. ^{[3
]}

Takata, Minoru ^{[1
,2
]}

机构：

[1] Kyoto Univ, Ctr Radiat Biol, Dept Late Effect Studies, Lab DNA Damage Signaling,Sakyo Ku, Kyoto 6068501, Japan

[2] Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Human Genet, Minami Ku, Hiroshima 7348553, Japan

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

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

[5] Hiroshima Univ, Grad Sch Biomed Sci, Dept Funct Mol Sci, Minami Ku, Hiroshima 7348553, Japan

[6] Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Cellular Biol, Minami Ku, Hiroshima 7348553, Japan

来源：

NATURE STRUCTURAL & MOLECULAR BIOLOGY | 2008年 / 15卷 / 11期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1038/nsmb.1504

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：

In response to DNA damage or replication fork stress, the Fanconi anemia pathway is activated, leading to monoubiquitination of FANCD2 and FANCI and their colocalization in foci. Here we show that, in the chicken DT40 cell system, multiple alanine-substitution mutations in six conserved and clustered Ser/Thr-Gln motifs of FANCI largely abrogate monoubiquitination and focus formation of both FANCI and FANCD2, resulting in loss of DNA repair function. Conversely, FANCI carrying phosphomimic mutations on the same six residues induces constitutive monoubiquitination and focus formation of FANCI and FANCD2, and protects against cell killing and chromosome breakage by DNA interstrand cross-linking agents. We propose that the multiple phosphorylation of FANCI serves as a molecular switch in activation of the Fanconi anemia pathway. Mutational analysis of putative phosphorylation sites in human FANCI indicates that this switch is evolutionarily conserved.

引用

页码：1138 / 1146

页数：9

共 38 条

[1] ATR couples FANCD2 monoubiquitination to the DNA-damage response [J].