Human SLX4 is a Holliday junction resolvase subunit that binds multiple DNA repair/recombination endonucleases.
Structure-specific endonucleases resolve DNA secondary structures generated during DNA repair and recombination. The yeast 5' flap endonuclease Slx1-Slx4 has received particular attention with the finding that Slx4 has Slx1-independent key functions in genome maintenance. Although Slx1 is a highly conserved protein in eukaryotes, no orthologs of Slx4 were reported other than in fungi. Here we report the identification of Slx4 orthologs in metazoa, including fly MUS312, essential for meiotic recombination, and human BTBD12, an ATM/ATR checkpoint kinase substrate. Human SLX1-SLX4 displays robust Holliday junction resolvase activity in addition to 5' flap endonuclease activity. Depletion of SLX1 and SLX4 results in 53BP1 foci accumulation and H2AX phosphorylation as well as cellular hypersensitivity to MMS. Furthermore, we show that SLX4 binds the XPF(ERCC4) and MUS81 subunits of the XPF-ERCC1 and MUS81-EME1 endonucleases and is required for DNA interstrand crosslink repair. We propose that SLX4 acts as a docking platform for multiple structure-specific endonucleases.
Fekairi
Samira
S
Genome Instability and Carcinogenesis UPR3081 CNRS, Conventionné par l'Université d'Aix-Marseille 2, IGC, IMM 31 chemin Joseph Aiguier, 13402 Marseille, France.
Scaglione
Sarah
S
Chahwan
Charly
C
Taylor
Ewan R
ER
Tissier
Agnès
A
Coulon
Stéphane
S
Dong
Meng-Qiu
MQ
Ruse
Cristian
C
Yates
John R
JR
Russell
Paul
P
Fuchs
Robert P
RP
McGowan
Clare H
CH
Gaillard
Pierre-Henri L
PHL
D000595:Amino Acid Sequence; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D004706:Endodeoxyribonucleases; D004720:Endonucleases / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D008969:Molecular Sequence Data; D045522:Recombinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic; D016415:Sequence Alignment
D004268:DNA-Binding Proteins; D045522:Recombinases; C095888:xeroderma pigmentosum group F protein; C071447:ERCC1 protein, human; D004706:Endodeoxyribonucleases; D004720:Endonucleases; C498772:MUS81 protein, human; C542320:SLX1 protein, human; C542319:SLX4 protein, human