The remaining flap, which is too short to support RPA binding, is then processed by FEN1. There is evidence that binding of RPA to the displaced end of the RNA-containing Okazaki fragment prevents FEN1 from accessing the substrate. FEN1 is a structure-specific endonuclease that cleaves near the base of the flap at a position one nucleotide into the annealed region. Biochemical studies have shown that the preferred substrate for FEN1 consists of a one-nucleotide 3'-tail on the upstream primer in addition to the 5'-flap of the downstream primer (Harrington and Lieber 1994, Harrington and Lieber 1995, Murante et al. 1996, Lieber 1997, Kaiser et al. 1999, Xu et al. 2000, Kao et al. 2002). The interaction of FEN1 with WRN, a RECQ family DNA helicase, is needed for successful flap cleavage during telomeric strand displacement synthesis (Saharia et al. 2010, Li et al. 2017).