The Shu complex interacts with the replicative helicase to prevent mutations and aberrant recombination

Adeola A Fagunloye; Alessio De Magis; Jordan H Little; Isabela Contreras; Tanis J Dorwart; Braulio Bonilla; Kushol Gupta; Nathan Clark; Theresa Zacheja; Katrin Paeschke; Kara A Bernstein

doi:10.1038/s44318-025-00365-9

The Shu complex interacts with the replicative helicase to prevent mutations and aberrant recombination

EMBO J. 2025 Jan 21. doi: 10.1038/s44318-025-00365-9. Online ahead of print.

Authors

Adeola A Fagunloye^#¹, Alessio De Magis^#^{2

3}, Jordan H Little⁴, Isabela Contreras¹, Tanis J Dorwart¹, Braulio Bonilla⁵, Kushol Gupta¹, Nathan Clark^{4

6}, Theresa Zacheja³, Katrin Paeschke^#^{7

8}, Kara A Bernstein^#⁹

Affiliations

¹ University of Pennsylvania, School of Medicine, Department of Biochemistry and Biophysics, Philadelphia, PA, 19104, USA.
² Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany.
³ Department of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
⁴ University of Utah, Department of Human Genetics, Salt Lake City, UT, 84112, USA.
⁵ University of Pittsburgh, School of Medicine, Department of Pharmacology and Chemical Biology, Pittsburgh, PA, 15213, USA.
⁶ University of Pittsburgh, Department of Biological Sciences, Pittsburgh, PA, 15260, USA.
⁷ Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany. [email protected].
⁸ Department of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany. [email protected].
⁹ University of Pennsylvania, School of Medicine, Department of Biochemistry and Biophysics, Philadelphia, PA, 19104, USA. [email protected].

^# Contributed equally.

PMID: 39838174
DOI: 10.1038/s44318-025-00365-9

Abstract

Homologous recombination (HR) is important for DNA damage tolerance during replication. The yeast Shu complex, a conserved homologous recombination factor, prevents replication-associated mutagenesis. Here we examine how yeast cells require the Shu complex for coping with MMS-induced lesions during DNA replication. We find that Csm2, a subunit of the Shu complex, binds to autonomous-replicating sequences (ARS) in yeast. Further evolutionary studies reveal that the yeast and human Shu complexes have co-evolved with specific replication-initiation factors. The connection between the Shu complex and replication is underlined by the finding that the Shu complex interacts with the ORC and MCM complexes. For example, the Shu complex interacts, independent of other HR proteins, with the replication initiation complexes through the N-terminus of Psy3. Lastly, we show interactions between the Shu complex and the replication initiation complexes are essential for resistance to DNA damage, to prevent mutations and aberrant recombination events. In our model, the Shu complex interacts with the replication machinery to enable error-free bypass of DNA damage.

Keywords: DNA Damage Tolerance; DNA Replication; Homologous Recombination; RAD51; Shu Complex.

Abstract

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