Search and localization dynamics of the CRISPR/Cas9 system

TL;DR

This paper models how the Cas9 protein searches for specific DNA targets, revealing that it primarily slides over short distances and exploring its behavior through a physics-inspired approach to match experimental data.

Contribution

It introduces a facilitated diffusion model for Cas9, fitting parameters to experiments and applying Anderson localization theory to understand its DNA search dynamics.

Findings

Cas9 searches by sliding with short sliding lengths

Theoretical model matches experimental distribution of Cas9 on DNA

Mapping to Anderson localization explains search behavior

Abstract

The CRISPR/Cas9 system acts as the prokaryotic immune system and has important applications in gene editing. The protein Cas9 is one of its crucial components. The role of Cas9 is to search for specific target sequences on the DNA and cleave them. In this Letter, we introduce a model of facilitated diffusion for Cas9 and fit its parameters to single-molecule experiments. Our model confirms that Cas9 search for targets by sliding, but shows that its sliding length is rather short. We then investigate how Cas9 explores a long stretch of DNA containing randomly placed targets. We solve this problem by mapping it into the theory of Anderson localization in condensed matter physics. Our theoretical approach rationalizes experimental evidences on the distribution of Cas9 molecules along the DNA.