The Fanconi Anemia Pathway Promotes Replication-Dependent DNA Interstrand Cross-Link Repair

被引：417

作者：

Knipscheer, Puck ^{[1
]}

Raeschle, Markus ^{[2
]}

Smogorzewska, Agata ^{[3
,4
,5
]}

Enoiu, Milica ^{[6
]}

Ho, The Vinh ^{[7
,8
]}

Schaerer, Orlando D. ^{[6
,7
,8
]}

Elledge, Stephen J. ^{[3
,4
]}

Walter, Johannes C. ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[2] Max Planck Inst Biochem, Dept Mol Cell Biol, D-82152 Martinsried, Germany

[3] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[4] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA

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

[6] Univ Zurich, Inst Mol Canc Res, CH-8057 Zurich, Switzerland

[7] SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USA

[8] SUNY Stony Brook, Dept Chem, Stony Brook, NY 11794 USA

来源：

SCIENCE | 2009年 / 326卷 / 5960期

关键词：

MONOUBIQUITINATED FANCD2; S-PHASE; PROTEINS;

D O I：

10.1126/science.1182372

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Fanconi anemia is a human cancer predisposition syndrome caused by mutations in 13 Fanc genes. The disorder is characterized by genomic instability and cellular hypersensitivity to chemicals that generate DNA interstrand cross-links (ICLs). A central event in the activation of the Fanconi anemia pathway is the mono-ubiquitylation of the FANCI-FANCD2 complex, but how this complex confers ICL resistance remains enigmatic. Using a cell-free system, we showed that FANCI-FANCD2 is required for replication-coupled ICL repair in S phase. Removal of FANCD2 from extracts inhibits both nucleolytic incisions near the ICL and translesion DNA synthesis past the lesion. Reversal of these defects requires ubiquitylated FANCI-FANCD2. Our results show that multiple steps of the essential S-phase ICL repair mechanism fail when the Fanconi anemia pathway is compromised.

引用

页码：1698 / 1701

页数：4

共 17 条

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