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Relocation of Collapsed Forks to the Nuclear Pore Complex Depends on Sumoylation of DNA Repair Proteins and Permits Rad51 Association

49 Pages Posted: 23 Jan 2020 Publication Status: Published

See all articles by Jenna M. Whalen

Jenna M. Whalen

Tufts University - Department of Biology

Nalini Dhingra

Memorial Sloan Kettering Cancer Center - Molecular Biology Program

Lei Wei

Memorial Sloan Kettering Cancer Center - Molecular Biology Program

Xiaolan Zhao

Memorial Sloan Kettering Cancer Center - Molecular Biology Program

Catherine Freudenreich

Tufts University - Department of Biology

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Abstract

Expanded CAG repeats form stem-loop secondary structures that lead to fork stalling and collapse. Previous work has shown that these collapsed forks relocalize to nuclear pore complexes (NPCs) in late S phase in a manner dependent on replication, the nucleoporin Nup84 and the Slx5 protein, which prevents repeat fragility and instability. We now show that binding of the Smc5/6 complex to the collapsed fork triggers Mms21-dependent sumoylation of fork-associated DNA repair proteins, and that RPA, Rad52, and Rad59 are the key sumoylation targets which mediate relocation. The SUMO interacting motifs of Slx5 target collapsed forks to the NPC. Notably, Rad51 foci only co-localize with the repeat after it is anchored to the nuclear periphery and Rad51 exclusion from the early collapsed fork is dependent on RPA sumoylation. This pathway may provide a mechanism to constrain recombination at stalled or collapsed forks until it is required for fork restart.

Keywords: replication fork, CAG repeat, RPA sumoylation, Smc5-Smc6, nuclear pore complex

Suggested Citation

Whalen, Jenna M. and Dhingra, Nalini and Wei, Lei and Zhao, Xiaolan and Freudenreich, Catherine, Relocation of Collapsed Forks to the Nuclear Pore Complex Depends on Sumoylation of DNA Repair Proteins and Permits Rad51 Association. Available at SSRN: https://ssrn.com/abstract=3523272 or http://dx.doi.org/10.2139/ssrn.3523272
This version of the paper has not been formally peer reviewed.

Jenna M. Whalen

Tufts University - Department of Biology

Medford, MA 02155
United States

Nalini Dhingra

Memorial Sloan Kettering Cancer Center - Molecular Biology Program

New York, NY 10065
United States

Lei Wei

Memorial Sloan Kettering Cancer Center - Molecular Biology Program

New York, NY 10065
United States

Xiaolan Zhao

Memorial Sloan Kettering Cancer Center - Molecular Biology Program

New York, NY 10065
United States

Catherine Freudenreich (Contact Author)

Tufts University - Department of Biology ( email )

Medford, MA 02155
United States

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