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

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

  • Cell. 2009 Jul 10;138(1):63-77. doi: 10.1016/j.cell.2009.06.030.
Jennifer M Svendsen 1,  Agata Smogorzewska,  Mathew E Sowa,  Brenda C O'Connell,  Steven P Gygi,  Stephen J Elledge,  J Wade Harper
Affiliations

Affiliation

  • 1 Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
PMID: 19596235 DOI: 10.1016/j.cell.2009.06.030
Abstract

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.

Figures