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Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair.

Structure-specific endonucleases mediate cleavage of DNA structures formed during repair of collapsed replication forks and double-strand breaks (DSBs). Here, we identify BTBD12 as the human ortholog of the budding yeast DNA repair factor Slx4p and D. melanogaster MUS312. Human SLX4 forms a multiprotein complex with the ERCC4(XPF)-ERCC1, MUS81-EME1, and SLX1 endonucleases and also associates with MSH2/MSH3 mismatch repair complex, telomere binding complex TERF2(TRF2)-TERF2IP(RAP1), the protein kinase PLK1 and the uncharacterized protein C20orf94. Depletion of SLX4 causes sensitivity to mitomycin C and camptothecin and reduces the efficiency of DSB repair in vivo. SLX4 complexes cleave 3' flap, 5' flap, and replication fork structures; yet unlike other endonucleases associated with SLX4, the SLX1-SLX4 module promotes symmetrical cleavage of static and migrating Holliday junctions (HJs), identifying SLX1-SLX4 as a HJ resolvase. Thus, SLX4 assembles a modular toolkit for repair of specific types of DNA lesions and is critical for cellular responses to replication fork failure.

Pubmed ID: 19596235

Authors

  • Svendsen JM
  • Smogorzewska A
  • Sowa ME
  • O'Connell BC
  • Gygi SP
  • Elledge SJ
  • Harper JW

Journal

Cell

Publication Data

July 10, 2009

Associated Grants

  • Agency: NIA NIH HHS, Id: R01 AG011085
  • Agency: NIA NIH HHS, Id: R01 AG011085-16
  • Agency: NIGMS NIH HHS, Id: R01 GM070565
  • Agency: NIGMS NIH HHS, Id: R01 GM070565-04
  • Agency: NCI NIH HHS, Id: T32CA09216
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Cell Line
  • DNA Breaks, Double-Stranded
  • DNA Damage
  • DNA Repair
  • DNA Replication
  • DNA-Binding Proteins
  • Endonucleases
  • Humans
  • Multiprotein Complexes
  • Recombinases