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Mol Cell. 2019 Aug 28. pii: S1097-2765(19)30619-7. doi: 10.1016/j.molcel.2019.08.003. [Epub ahead of print]

SUMO-Chain-Regulated Proteasomal Degradation Timing Exemplified in DNA Replication Initiation.

Author information

1
IFOM, FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy.
2
IFOM, FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy; Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche (IGM-CNR), Via Abbiategrasso 207, 27100 Pavia, Italy. Electronic address: dana.branzei@ifom.eu.

Abstract

Similar to ubiquitin, SUMO forms chains, but the identity of SUMO-chain-modified factors and the purpose of this modification remain largely unknown. Here, we identify the budding yeast SUMO protease Ulp2, able to disassemble SUMO chains, as a DDK interactor enriched at replication origins that promotes DNA replication initiation. Replication-engaged DDK is SUMOylated on chromatin, becoming a degradation-prone substrate when Ulp2 no longer protects it against SUMO chain assembly. Specifically, SUMO chains channel DDK for SUMO-targeted ubiquitin ligase Slx5/Slx8-mediated and Cdc48 segregase-assisted proteasomal degradation. Importantly, the SUMOylation-defective ddk-KR mutant rescues inefficient replication onset and MCM activation in cells lacking Ulp2, suggesting that SUMO chains time DDK degradation. Using two unbiased proteomic approaches, we further identify subunits of the MCM helicase and other factors as SUMO-chain-modified degradation-prone substrates of Ulp2 and Slx5/Slx8. We thus propose SUMO-chain/Ulp2-protease-regulated proteasomal degradation as a mechanism that times the availability of functionally engaged SUMO-modified protein pools during replication and beyond.

KEYWORDS:

Cdc48 segregase; DDK; DNA replication; SENP/Ulp proteases; STUbL-mediated proteasomal degradation; SUMO; SUMO chains; Slx5/8; protein-group modification; ubiquitin

PMID:
31519521
DOI:
10.1016/j.molcel.2019.08.003
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