Induced degradation of Ufd1 reveals regulation of cohesin by the VCP/p97Ufd1-Npl4 complex.

Daniella Munro; Maike Reinders; Aikaterini Pravi; Johannes van den Boom; Pinki Gahlot; Ekaterina Isaakova; Caio Ab Oliveira; Dominik Boos; Petra Beli; Hemmo Meyer

doi:10.26508/lsa.202603698

PubMed · 42692794

Induced degradation of Ufd1 reveals regulation of cohesin by the VCP/p97Ufd1-Npl4 complex.

Daniella Munro·Maike Reinders·Aikaterini Pravi·Johannes van den Boom·Pinki Gahlot·Ekaterina Isaakova·Caio Ab Oliveira·Dominik Boos·Petra Beli·Hemmo Meyer

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Abstract

The AAA ATPase VCP/p97 has emerged as a critical regulator of ubiquitin and chromatin-associated processes but progress in understanding has been hampered by the complexity of p97 functions and the various p97 cofactors involved. Here, we combined ubiquitin profiling with acutely induced degradation of the Ufd1 subunit of the p97 ubiquitin adapter, Ufd1-Npl4, in human cells. We identified a set of chromatin regulators, HUS1, XRCC1, MORF4L1, and the cohesin subunit RAD21 as targets of p97Ufd1-Npl4 We find that RAD21 is ubiquitylated and targeted by p97Ufd1-Npl4 specifically in S phase to remove a subpopulation of cohesin from chromatin. Acute degradation of Ufd1 in S phase, after replication licensing is completed, impedes replication and leads to replication-associated DNA damage. Our findings suggest that a fraction of cohesin rings need to be removed by p97Ufd1-Npl4 from DNA to allow unhindered replication and reveal a critical function of p97 that ensures genome stability.

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Cell Cycle Proteins Chromosomal Proteins, Non-Histone Humans Valosin Containing Protein Cohesins Nuclear Proteins Adenosine Triphosphatases DNA Replication Chromatin DNA Damage Proteolysis Ubiquitination S Phase Phosphoproteins DNA-Binding Proteins Intracellular Signaling Peptides and Proteins Journal Article

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Daniella Munro, Maike Reinders, Aikaterini Pravi, Johannes van den Boom, Pinki Gahlot, Ekaterina Isaakova, Caio Ab Oliveira, Dominik Boos, Petra Beli, Hemmo Meyer. 2026-09-03. Induced degradation of Ufd1 reveals regulation of cohesin by the VCP/p97Ufd1-Npl4 complex.. https://doi.org/10.26508/lsa.202603698

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