Ring of Change: CDC48/p97 Drives Protein Dynamics at Chromatin

Abstract

The dynamic composition of proteins associated with nuclear DNA is a fundamental property of chromosome biology. In the chromatin compartment dedicated protein complexes govern the accurate synthesis and repair of the genomic information and define the state of DNA compaction in vital cellular processes such as chromosome segregation or transcription. Unscheduled or faulty association of protein complexes with DNA has detrimental consequences on genome integrity. Consequently, the association of protein complexes with DNA is remarkably dynamic and can respond rapidly to cellular signaling events, which requires tight spatiotemporal control. In this context, the ring-like AAA+ ATPase CDC48/p97 emerges as a key regulator of protein complexes that are marked with ubiquitin or SUMO. Mechanistically, CDC48/p97 functions as a segregase facilitating the extraction of substrate proteins from the chromatin. As such, CDC48/p97 drives molecular reactions either by directed disassembly or rearrangement of chromatin-bound protein complexes. The importance of this mechanism is reflected by human pathologies linked to p97 mutations, including neurodegenerative disorders, oncogenesis, and premature aging. This review focuses on the recent insights into molecular mechanisms that determine CDC48/p97 function in the chromatin environment, which is particularly relevant for cancer and aging research.

Keywords: CDC48; DNA repair; SUMO; chromatin; p97; replication; ubiquitin.

FIGURE 1

CDC48/p97 function in chromatin-associated processes. (A) Schematic illustration of molecular mechanisms underlying CDC48/p97 activity. CDC48/p97 (red) recognizes chromatin-bound substrates (blue) that are conjugated to ubiquitin or SUMO (black circles). The modification with ubiquitin and SUMO can come in different flavors (exemplified by a chain of molecules). Both molecules can be conjugated as a monomeric moiety or a chain of several molecules. The linkage in between molecules of a ubiquitin chain is variable depending on the internal lysine-(K)-residue used for chain extension (indicated by the angle between ubiquitin molecules of a chain). As such, diverse linkages are capable of defining distinct signaling events (referred to as ‘ubiquitin-code’). Moreover, SUMO-dependent ubiquitylation gives rise to hybrid chains. Depending on the exact modification of the substrates, diverse cofactors facilitate substrate recognition and/or processing of the ubiquitin/SUMO modification by extending, removing, or internal remodeling of the chain. This is probably important to define the directionality of the CDC48/p97 reaction. Eventually, CDC48/p97 segregase activity is required to mobilize the substrate from higher order protein complexes (light gray). On one hand the substrate can be recycled, probably involving hydrolysis of the modification. Otherwise, the substrate can be terminally degraded involving the proteasome, lysosome, or proteolytic cofactors. Extraction of the substrate can promote two distinct outcomes. Disintegration of the protein complex can result in its inactivation (bottom left). Alternatively, extraction of the substrate can disclose the binding site of another factor (orange) thus facilitating the directed progression of the reaction (bottom right). (B) Schematic overview of CDC48/p97-dependent pathways in the context of eukaryotic chromosomes (gray). CDC48/p97 (red) possesses molecular switch properties, driving molecular reactions in distinct chromatin-associated processes. The involvement of respective CDC48/p97 cofactors is listed below the indicated pathways.