Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia.
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.
Medical Research Council, Laboratory of Molecular Biology, Cambridge, UK.
Gerry P
GP
Crossan
Louise
L
van der Weyden
Ivan V
IV
Rosado
Frederic
F
Langevin
Pierre-Henri L
PHL
Gaillard
Rebecca E
RE
McIntyre
Ferdia
F
Gallagher
Mikko I
MI
Kettunen
David Y
DY
Lewis
Kevin
K
Brindle
Mark J
MJ
Arends
David J
DJ
Adams
Ketan J
KJ
Patel
D000818:Animals; D016922:Cellular Senescence; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004249:DNA Damage; D005199:Fanconi Anemia / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005816:Genetic Complementation Test; D006412:Hematopoietic Stem Cells; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D045522:Recombinases / Q000235:genetics* / Q000502:physiology*
D003432:Cross-Linking Reagents; D045522:Recombinases; C543807:Slx4 protein, mouse
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