A tale of two forms of cohesin in DNA repair Extrusive and cohesive cohesin cooperate to repair double-strand breaks in DNA

Extrusive and cohesive cohesin cooperate to repair double-strand breaks in DNA.

Learn more in a new #SciencePerspective: https://scim.ag/3XKbhb6

Thank you, Federico! And congratulations to you too! The studies complement each other quite nicely, indeed.

Thank you, Prof. Ramsden!

Thanks, Jan! Congratulations to you too. Really amazing work!

Last but not least, I am incredibly grateful to my mentor, Taekjip Ha, for giving me the freedom to take risks and for guiding me throughout the project. And co-mentor, Ralph Scully, for all his support and mentorship. 11/n

Big thanks to our amazing team – especially co-first authors Adam and @namratan.bsky.social who put so much work into this project. It’s been a huge privilege to work with you. 10/n

Cohesin guides homology search during DNA repair using loops and sister chromatid linkages Accurate repair of DNA double-strand breaks (DSBs) is essential for genome stability, and defective repair underlies diseases such as cancer. Homologous recombination uses an intact homologous sequenc...

Also, check out the related work by @fedeteloni.bsky.social et al, from @gerlichlab.bsky.social who looked at the role of cohesive cohesin as well.
www.science.org/doi/10.1126/...
And the insightful perspective by Jiazhi Hu! 9/n
www.science.org/doi/10.1126/...

Cohesin drives chromatin scanning during the RAD51-mediated homology search Cohesin folds genomes into chromatin loops, the roles of which are under debate. We found that double-strand breaks (DSBs) induce de novo formation of chromatin loops in human cells, with the loop bas...

Link to the publication below! 8/n
www.science.org/doi/10.1126/...

Thus, chromatin loops don’t just organize the genome to control gene expression – they also protect its integrity by helping a broken DNA find its matching sequence for repair! 7/n

We discovered that instead of searching randomly, cells use an active 1D scanning process: the repair machinery leverages a looping protein called cohesin to ‘slide’ the break along the DNA and find the matching sequence. 6/n

Simply relying on random 3D diffusion – letting the broken DNA wander through the nucleus – would be inefficient. Even for a 1 Mb region, the broken DNA would take far too long to find its matching sequence by chance alone. 5/n

Now, after DNA replicates, sister chromatids are held together approximately every 1 Mb so the search is confined to ~1 M nucleotides. But finding the right match is still a huge challenge – especially if the sisters aren’t perfectly aligned. 4/n

Homologous recombination is key for protecting the genome, but it’s also challenging because the broken DNA must find its matching copy within billions of nucleotides. How can a cell achieve this? This is known as the “homology search” problem. 3/n

When DNA breaks, cells often repair it through a process called homologous recombination, in which a matching (replicated) copy of the broken sequence is used as a repair template. 2/n

Cohesin drives chromatin scanning during the RAD51-mediated homology search Cohesin folds genomes into chromatin loops, the roles of which are under debate. We found that double-strand breaks (DSBs) induce de novo formation of chromatin loops in human cells, with the loop bas...

Thrilled to share that my postdoc research is published today in @science.org! We found that DNA repair uses cohesin complexes to build new chromatin loops that guide the homology search and boost accurate repair! 1/n
www.science.org/doi/10.1126/...

A tale of two forms of cohesin in DNA repair Extrusive and cohesive cohesin cooperate to repair double-strand breaks in DNA

And the insightful perspective by Jiazhi Hu! 10/n
www.science.org/doi/10.1126/...

Cohesin guides homology search during DNA repair using loops and sister chromatid linkages Accurate repair of DNA double-strand breaks (DSBs) is essential for genome stability, and defective repair underlies diseases such as cancer. Homologous recombination uses an intact homologous sequenc...

Also, check out the related study by @fedeteloni.bsky.social from @gerlichlab.bsky.social where they also looked at the role of cohesive cohesin! 9/n
www.science.org/doi/10.1126/...

Link to the publication below! 8/n
www.science.org/doi/10.1126/...

Thus, chromatin loops don’t just organize the genome to control gene expression – they also protect its integrity by helping a broken DNA find its matching sequence for repair! 7/n

We discovered that instead of searching randomly, cells use an active 1D scanning process: the repair machinery leverages a looping protein called cohesin to ‘slide’ the break along the DNA and find the matching sequence. 6/n

Simply relying on random 3D diffusion – letting the broken DNA wander through the nucleus – would be inefficient. Even for a 1 Mb region, the broken DNA would take far too long to find its matching sequence by chance alone. 5/n

Now, after DNA replicates, sister chromatids are held together approximately every 1 Mb so the search is confined to ~1 M nucleotides. But finding the right match is still a huge challenge – especially if the sisters aren’t perfectly aligned. 4/n

Homologous recombination is key for protecting the genome, but it’s also challenging because the broken DNA must find its matching copy within billions of nucleotides. How can a cell achieve this? This is know as the “homology search” problem. 3/n

When DNA breaks, cells often repair it through a process called homologous recombination, in which a matching (replicated) copy of the broken sequence is used as a repair template. 2/n

Cohesin guides homology search during DNA repair via loops and sister chromatid linkages Accurate repair of DNA double-strand breaks (DSBs) is essential for genome stability, and defective repair underlies diseases such as cancer. Homologous recombination uses an intact homologous sequenc...

15/n
Also, check out the pre-prints by @fedeteloni.bsky.social from @gerlichlab.bsky.social and by @charlesyeh.bsky.social from @jcornlab.bsky.social with other cool insights about the homology search!
www.biorxiv.org/content/10.1...
www.biorxiv.org/content/10.1...

14/n
I also want to thank all the other authors: Daniel Nguyen, Violetta Karwacki-Neisius, Andrew G. Li, Roger Zou, Franklin Aviles-Vazquez and Masato Kanemaki.

And huge thanks to Yang Liu who made vfCRISPR and to
@nucleosomezky.bsky.social and @rezakalhor.bsky.social for discussions!

13/n
Incredibly thankful to my mentor, Taekjip Ha, who supervised and mentored me on this project,

to my co-mentor, Ralph Scully, who designed the mESC exps and mentored me on HR,

and to co-first authors Adam Rybczynski and Namrata Nilavar, who helped make this possible!

12/n
Our model, in a nutshell: cohesin drives homology search via 1D scanning.

During HR, a RAD51 filament locally scans the sister chromatid, but this search could be unproductive (e.g., because the donor is far).

Cohesin loops would then facilitate long-range scanning to help find a donor!