Methods for improved homologous recombination and compositions thereof

A method of enhancing activity of a modulating protein or a modulating complex at a target locus in a cell, the method comprising:

• (1) introducing into a cell comprising a nucleic acid encoding the target locus:
• (i) a first modulating protein or a first modulating complex capable of binding a first modulator binding sequence of the target locus, wherein the first modulator binding sequence comprises a modulation site;
• wherein the activity of the first modulating protein or the first modulating complex is a nuclease or other enzymatic activity, and
• (ii) a first DNA-binding modulation-enhancing agent without nuclease or other enzymatic activity comprising a nuclear localization signal and a DNA-binding domain that is capable of binding a first enhancer binding sequence of the target locus;
• and
• (2) allowing the first DNA-binding modulation-enhancing agent to bind the first enhancer binding sequence, thereby enhancing activity of the first modulating protein or the first modulating complex at the target locus in the cell,
• wherein the DNA-binding modulation-enhancing agent is not fused with, covalently linked with, or linked by dimerization with the first modulating protein or first modulating complex of (i), a modulating protein, modulating complex, or other DNA-binding agent.