Excited to share our latest pre-print:
www.biorxiv.org/content/10.6...
where we built a biophysical polymer model of the mammalian homology search. This work was led by Tylar Matsuo, an outstanding post-bac student in the Ha lab that I have had the pleasure to mentor. Here is what we found. 1/n
Link to the bioRxiv below! Thanks again to Tylar Matsuo, for his incredible work, and to Taekjip Ha, for his support and mentorship. 9/n
www.biorxiv.org/content/10.6...
After DNA replication, cells activate a mechanism to fix DNA breaks known as homologous recombination (HR), which restores a broken site using its replicated copy as template. HR is powerful, but it presents a unique challenge: the broken locus needs to search for and find its replicated locus. 2/n
Recent works by us and others have shed light into these genomic searches, revealing that they are stimulated by the chromatin looping activity of the cohesin complex. But many questions remained unanswered. What are the dynamics of the process? How does loop extrusion stimulate the search? 3/n
Cohesin effects were more pronounced when we simulated searches along a large TAD (~1 Mb), where diffusion alone is inefficient. Hence, cohesin might be especially important in stimulating HR for breaks occuring in large TADs, that likely require more extended searches. 6/n
A surprising finding: removing loops in the broken chromatid had a small effect in search dynamics. It is the loops in the sister chromatid that play a dominant role in lowering search times! We looked at individual search instances to understand this. 7/n
First, housekeeping cohesins accelerates the search by over 4x compared to 3D diffusion alone; adding break-interacting cohesins (break-anchored loops and cohesive clamp) boost the search by an additional 2x. Thus, searches are approx. an order of magnitude faster when cohesins are present! 5/n
Here, we used polymer simulations to model the homology search on a replicated TAD. Our simulations recapitulate key experimental findings (RAD51 ChIP-Seq profiles, chromosome contacts and HR efficiency) and reveal new insights into how cohesin promotes homology searches. 4/n
Alberto Marin
We found that loops on the broken chromatid promote the initial encounter between the break and the sister chromatid by steering the break toward TAD boundaries. Loops on the sister chromatid drive the subsequent 1D scanning that is the rate-limiting step for homology identification. 8/n
Extrusive and cohesive cohesin cooperate to repair double-strand breaks in DNA.
Learn more in a new #SciencePerspective: https://scim.ag/3XKbhb6
