4.8 Article

FAN1 Activity on Asymmetric Repair Intermediates Is Mediated by an Atypical Monomeric Virus-type Replication-Repair Nuclease Domain

Journal

CELL REPORTS
Volume 8, Issue 1, Pages 84-93

Publisher

CELL PRESS
DOI: 10.1016/j.celrep.2014.06.001

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Funding

  1. Medical Research Council, UK [U117584228]
  2. Cancer Research UK
  3. BBSRC [BB/E001777/1] Funding Source: UKRI
  4. EPSRC [EP/J017094/1] Funding Source: UKRI
  5. MRC [MC_U117565647, MC_U117584228, MC_U127070192, MC_UU_12016/1] Funding Source: UKRI
  6. Biotechnology and Biological Sciences Research Council [BB/E001777/1] Funding Source: researchfish
  7. Cancer Research UK [11722] Funding Source: researchfish
  8. Engineering and Physical Sciences Research Council [EP/J017094/1] Funding Source: researchfish
  9. Medical Research Council [MC_U117584228, MC_U127070192, MC_UU_12016/1, MC_U117565647] Funding Source: researchfish

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FAN1 is a structure-selective DNA repair nuclease with 5' flap endonuclease activity, involved in the repair of interstrand DNA crosslinks. It is the only eukaryotic protein with a virus-type replication-repair nuclease (VRR-Nuc'') module'' that commonly occurs as a standalone domain in many bacteria and viruses. Crystal structures of three representatives show that they structurally resemble Holliday junction resolvases (HJRs), are dimeric in solution, and are able to cleave symmetric four-way junctions. In contrast, FAN1 orthologs are monomeric and cleave 5' flap structures in vitro, but not Holliday junctions. Modeling of the VRR-Nuc domain of FAN1 reveals that it has an insertion, which packs against the dimerization interface observed in the structures of the viral/bacterial VRR-Nuc proteins. We propose that these additional structural elements in FAN1 prevent dimerization and bias specificity toward flap structures.

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