Figure 3. Hypothetical mechanisms allowing L1 RNA base-pairing with target-site DNA. (A) ORF2p dimerization leads to simultaneous staggered cuts through its EN activity. The resulting extremities have 3′ overhangs, which can anneal to the L1 RNA and prime L1 cDNA synthesis. (B) L1 EN initially starts with a single cut, but a DNA-dependent helicase unwinds the target site DNA strands, enabling L1 cDNA synthesis. (C) Upon double-strand DNA break, DNA repair factors resect these ends and generate 3′ overhangs. These new extremities not necessarily end with Ts as for EN sites. Consequently, base-pairing generally occurs at internal sites within the L1 RNA which show spurious matches with the damaged site. (D) Telomeres naturally end with 3′ overhangs. Red arrowhead, EN cut; green, cDNA; pink, L1 RNA.