Dual Recruitment of Cdc48 (p97)-Ufd1-Npl4 Ubiquitin-selective Segregase by Small Ubiquitin-like Modifier Protein (SUMO) and Ubiquitin in SUMO-targeted Ubiquitin Ligase-mediated Genome Stability Functions

Abstract

Background: SUMO-targeted ubiquitylation controls critical cellular processes, including genome stability; but effectors and mechanisms remain undefined. Results: The Cdc48-Ufd1-Npl4 segregase binds SUMO and cooperates with the SUMO-targeted ubiquitin ligase (STUbL) in DNA repair. Conclusion: Cdc48-Ufd1-Npl4 acts as a STUbL effector. Significance: Novel dual recognition of SUMO and ubiquitin co-modified proteins likely provides selectivity and specificity in signaling by these critical factors.

Pli1PIAS1 SUMO Ligase Protected by the Nuclear Pore-associated SUMO Protease Ulp1SENP1/2

“…We and others recently proposed a cooperative role for STUbL and Cdc48 (p97) AAA ϩ ATPase in the proteasomal degradation of SUMO conjugates, at a global level (44,45). Consistent with this proposal, mutations in the Cdc48 cofactor Ufd1 (ufd1-1) or in the 19S proteasome regulatory subunit Mts3 (mts3-1) also stabilized Pli1 in nup132⌬ cells (Fig.…”

“…In addition, Cdc48-Ufd1-Npl4 was recently identified as a cofactor for STUbL in managing global SUMO conjugate levels (44,45). However, evidence for a cooperative role in degrading a specific substrate was lacking.…”

“…As in fission yeast (44,45), budding yeast Cdc48 also acts as a SUMO-targeted segregase that removes sumoylated DNA repair factors from chromatin (59). Given this degree of functional conservation, it seems likely that the human STUbL RNF4 and p97 cooperate in the remodeling of chromatin e.g.…”

Conditional mutation of Smc5 in mouse embryonic stem cells perturbs condensin localization and mitotic progression

“…Furthermore, the persistence of Aurora B resulted in defects in chromosome congression and segregation, similar to what we observe in Smc5 mutant mESCs. The Ufd1 subunit of this chaperone complex has been shown to bind ubiquitin and small ubiquitin-like modifications (SUMO) (Nie et al, 2012). SUMO modification of Aurora B stimulates its removal from chromosome arms during prometaphase (Fernandez-Miranda et al, 2010).…”

The AAA-ATPase molecular chaperone Cdc48/p97 disassembles sumoylated centromeres, decondenses heterochromatin, and activates ribosomal RNA genes

“…To elucidate how CDC48A is targeted to sumoylated CenH3, we searched for adaptor proteins required for CDC48A function in pollen. Ufd1-Npl4, a known heterodimeric cofactor of Cdc48/p97 (17), binds to both ubiquitin and SUMO (18). The Arabidopsis genome encodes three Ufd1 homologs, which we named UFD1A (AT2g29070), UFD1B (AT2g21270), and UFD1C (AT4g38930), and two Npl4 homologs, which we named NPL4A (AT2g47970) and NPL4B (AT3g63000).…”