Importance of homo-dimerization of Fanconi-associated nuclease 1 in DNA flap cleavage

Timsi Rao, Simonne Longerich, Weixing Zhao, Hideki Aihara, Patrick Sung, Yong Xiong

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Fanconi-associated nuclease 1 (FAN1) removes interstrand DNA crosslinks (ICLs) through its DNA flap endonuclease and exonuclease activities. Crystal structures of human and bacterial FAN1 bound to a DNA flap have been solved. The Pseudomonas aeruginosa bacterial FAN1 and human FAN1 (hFAN1) missing a flexible loop are monomeric, while intact hFAN1 is homo-dimeric in structure. Importantly, the monomeric and dimeric forms of FAN1 exhibit very different DNA binding modes. Here, we interrogate the functional differences between monomeric and dimeric forms of FAN1 and provide an explanation for the discrepancy in oligomeric state between the two hFAN1 structures. Specifically, we show that the flexible loop in question is needed for hFAN1 dimerization. While monomeric and dimeric bacterial or human FAN1 proteins cleave a short 5′ flap strand with similar efficiency, optimal cleavage of a long 5′ flap strand is contingent upon protein dimerization. Our study therefore furnishes biochemical evidence for a role of hFAN1 homodimerization in biological processes that involve 5′ DNA Flap cleavage.

Original languageEnglish (US)
Pages (from-to)53-58
Number of pages6
JournalDNA Repair
StatePublished - Apr 2018

Bibliographical note

Funding Information:
We thank William Eliason for technical support in the SEC-MALLS analysis. This work was supported by National Institutes of Health Grants R01 ES007061 , RO1 CA168635 , R35 GM118047 and a Young Investigator Award from the Alex’s Lemonade Stand Foundation for Childhood Cancer .

Publisher Copyright:
© 2018 Elsevier B.V.


  • FA pathway
  • FAN1
  • ICL
  • Interstrand crosslink repair


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