The RAD52 double-ring remodels replication forks restricting fork reversal

Masayoshi Honda, Mortezaali Razzaghi, Paras Gaur, Eva Malacaria, Giorgia Marozzi, Ludovica Di Biagi, Francesca Antonella Aiello, Emeleeta A. Paintsil, Andrew J. Stanfield, Bailey J. Deppe, Lokesh Gakhar, Nicholas J. Schnicker, M. Ashley Spies, Pietro Pichierri and Maria Spies ()
Additional contact information
Masayoshi Honda: University of Iowa Carver College of Medicine
Mortezaali Razzaghi: University of Iowa Carver College of Medicine
Paras Gaur: University of Iowa Carver College of Medicine
Eva Malacaria: Istituto Superiore di Sanità
Giorgia Marozzi: Istituto Superiore di Sanità
Ludovica Di Biagi: Istituto Superiore di Sanità
Francesca Antonella Aiello: Istituto Superiore di Sanità
Emeleeta A. Paintsil: University of Iowa Carver College of Medicine
Andrew J. Stanfield: University of Iowa Carver College of Medicine
Bailey J. Deppe: University of Iowa Carver College of Medicine
Lokesh Gakhar: University of Iowa Carver College of Medicine
Nicholas J. Schnicker: University of Iowa
M. Ashley Spies: University of Iowa
Pietro Pichierri: Istituto Superiore di Sanità
Maria Spies: University of Iowa Carver College of Medicine

Nature, 2025, vol. 641, issue 8062, 512-519

Abstract: Abstract Human RAD52 is a multifunctional DNA repair protein involved in several cellular events that support genome stability, including protection of stalled DNA replication forks from excessive degradation1–4. In its gatekeeper role, RAD52 binds to and stabilizes stalled replication forks during replication stress, protecting them from reversal by SMARCAL1 motor3. The structural and molecular mechanism of the RAD52-mediated fork protection remains elusive. Here, using P1 nuclease sensitivity, biochemical and single-molecule analyses, we show that RAD52 dynamically remodels replication forks through its strand exchange activity. The presence of the single-stranded DNA binding protein RPA at the fork modulates the kinetics of the strand exchange without impeding the reaction outcome. Mass photometry and single-particle cryo-electron microscopy show that the replication fork promotes a unique nucleoprotein structure containing head-to-head arrangement of two undecameric RAD52 rings with an extended positively charged surface that accommodates all three arms of the replication fork. We propose that the formation and continuity of this surface is important for the strand exchange reaction and for competition with SMARCAL1.

Date: 2025
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DOI: 10.1038/s41586-025-08753-1

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