Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia

被引：166

作者：

Crossan, Gerry P. ^{[1
]}

van der Weyden, Louise ^{[2
]}

Rosado, Ivan V. ^{[1
]}

Langevin, Frederic ^{[1
]}

Gaillard, Pierre-Henri L. ^{[3
]}

McIntyre, Rebecca E. ^{[2
]}

Project, Sanger Mouse Genetics ^{[2
]}

Gallagher, Ferdia ^{[4
]}

Kettunen, Mikko I. ^{[4
]}

Lewis, David Y. ^{[4
]}

Brindle, Kevin ^{[4
]}

Arends, Mark J. ^{[5
]}

Adams, David J. ^{[2
]}

Patel, Ketan J. ^{[1
,6
]}

机构：

[1] MRC, Mol Biol Lab, Cambridge CB2 2QH, England

[2] Wellcome Trust Sanger Inst, Cambridge, England

[3] Convent Univ Aix Marseille 2, CNRS, Genome Instabil & Carcinogenesis UPR3081, Marseille, France

[4] Li Ka Shing Ctr, Cambridge Res Inst, Canc Res UK, Cambridge, England

[5] Univ Cambridge, Addenbrookes Hosp, Dept Pathol, Cambridge CB2 2QQ, England

[6] Univ Cambridge, Addenbrookes Hosp, Dept Med, Cambridge CB2 2QQ, England

来源：

NATURE GENETICS | 2011年 / 43卷 / 02期

基金：

英国惠康基金;

关键词：

STRUCTURE-SPECIFIC ENDONUCLEASE; HOLLIDAY JUNCTION RESOLVASE; REPAIR GENE ERCC1; DNA-REPAIR; DEFICIENT MICE; SPERMATOGENESIS; PROLIFERATION; ABNORMALITIES; SLX1-SLX4; PROTEIN;

D O I：

10.1038/ng.752

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The evolutionarily conserved SLX4 protein, a key regulator of nucleases, is critical for DNA damage response. SLX4 nuclease complexes mediate repair during replication and can also resolve Holliday junctions formed during homologous recombination. Here we describe the phenotype of the Btbd12 knockout mouse, the mouse ortholog of SLX4, which recapitulates many key features of the human genetic illness Fanconi anemia. Btbd12-deficient animals are born at sub-Mendelian ratios, have greatly reduced fertility, are developmentally compromised and are prone to blood cytopenias. Btbd12(-/-) cells prematurely senesce, spontaneously accumulate damaged chromosomes and are particularly sensitive to DNA crosslinking agents. Genetic complementation reveals a crucial requirement for Btbd12 (also known as Slx4) to interact with the structure-specific endonuclease Xpf-Ercc1 to promote crosslink repair. The Btbd12 knockout mouse therefore establishes a disease model for Fanconi anemia and genetically links a regulator of nuclease incision complexes to the Fanconi anemia DNA crosslink repair pathway.

引用

页码：147 / U99

页数：8

共 28 条

[1] BRCTx is a novel, highly conserved RAD18-interacting protein [J].