The AAA-ATPase p97-Ufd1-Npl4 is required for ERAD but not for spindle disassembly in <i>Xenopus</i> egg extracts

Heubes, Simone; Stemmann, Olaf

doi:10.1242/jcs.006924

Cited by 29 publications

(37 citation statements)

References 16 publications

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“…S3B to D). Second, we supplemented extract with buffer, wild-type p97 protein, or an ATPase-deficient p97 mutant (p97-DN) shown to act in a dominant-negative manner (45,52,53). Compared to wild-type p97, extract supplemented with p97-DN showed diminished ICL repair and delays in Cdc45 displacement and approach (see Fig.…”

Section: Resultsmentioning

confidence: 99%

p97 Promotes a Conserved Mechanism of Helicase Unloading during DNA Cross-Link Repair

Fullbright

Rycenga

Gruber

et al. 2016

Molecular and Cellular Biology

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Interstrand cross-links (ICLs) are extremely toxic DNA lesions that create an impassable roadblock to DNA replication. When a replication fork collides with an ICL, it triggers a damage response that promotes multiple DNA processing events required to excise the cross-link from chromatin and resolve the stalled replication fork. One of the first steps in this process involves displacement of the CMG replicative helicase (comprised of Cdc45, MCM2-7, and GINS), which obstructs the underlying crosslink. Here we report that the p97/Cdc48/VCP segregase plays a critical role in ICL repair by unloading the CMG complex from chromatin. Eviction of the stalled helicase involves K48-linked polyubiquitylation of MCM7, p97-mediated extraction of CMG, and a largely degradation-independent mechanism of MCM7 deubiquitylation. Our results show that ICL repair and replication termination both utilize a similar mechanism to displace the CMG complex from chromatin. However, unlike termination, repair-mediated helicase unloading involves the tumor suppressor protein BRCA1, which acts upstream of MCM7 ubiquitylation and p97 recruitment. Together, these findings indicate that p97 plays a conserved role in dismantling the CMG helicase complex during different cellular events, but that distinct regulatory signals ultimately control when and where unloading takes place. Interstrand cross-links (ICLs) are extremely toxic DNA lesions that covalently couple both strands of the DNA duplex. Replicating cells are particularly sensitive to ICLs, which disrupt the strand separation required for DNA replication and transcription (1). Repair of ICLs is initiated primarily during S phase when a replication fork collides with the cross-link (2-4). Fork stalling triggers a damage response that involves multiple DNA processing events that promote excision of the ICL from chromatin and resolution of the stalled replication fork (5). Defects in ICL repair are associated with delays in cell cycle progression, increased chromosomal breakage, and severe sensitivity to DNA cross-linking agents. The cellular symptoms of deficient or aberrant repair are thought to underlie the molecular basis of several cancer predisposition syndromes (6), including Fanconi anemia (FA) and hereditary breast and ovarian cancer.Fanconi anemia is a rare chromosomal instability disorder caused by mutations in 1 of at least 16 different genes (7). Four of the FA genes are classified as breast/ovarian cancer susceptibility (BRCA) genes (FANCD1/BRCA2, FANCJ/BRIP1, FANCN/ PALB2, FANCO/RAD51C) (8), with recent evidence also supporting classification of BRCA1 as a new FA subtype (FANCS) (9). Together, the FA/BRCA proteins and associated factors form a multifunctional network that plays a critical role in managing various forms of DNA damage and replication stress (10). Although both FA and BRCA proteins are required for ICL repair, each pathway also supports nonoverlapping functions (11, 12) that play different roles in how cells respond to treatment with DNA cross-linking agents.Xenop...

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Section: Resultsmentioning

confidence: 99%

p97 Promotes a Conserved Mechanism of Helicase Unloading during DNA Cross-Link Repair

Fullbright

Rycenga

Gruber

et al. 2016

Molecular and Cellular Biology

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“…Meanwhile another cytosolic protein complex have been found, containing an AAA-ATPase: the mammalian Cdc48p (also termed as p97 or VCP) (Goder et al, 2008;Shcherbik and Haines, 2007;Wilson et al, 2006) may be a key protein in the dislocation process. In complex with two other proteins, Npl4 and Ufd1 (Shcherbik and Haines, 2007;Lass et al, 2008;Cao et al, 2007) that bind ubiquitinated proteins, this complex (Cdc48p-Npl4-Ufd1) (Heubes and Stemmann, 2007;Nowis et al, 2006;Alzayady et al, 2005;Cao and Zheng, 2004) may be responsible for the breakdown of large protein complexes before proteolytic degradation of its elements. Experiments revealed that the process of translocation from ER by Cdc48p-Npl4-Ufd1 is ATP dependent; a comparable function has been attributed to chaperones of the Hsp70 family in importing newly synthesized proteins into the ER and mitochondria (Hood et al, 2003).…”

Section: Proteinsmentioning

confidence: 99%

The proteasomal system

Jung

Karademir

Grune

2009

Molecular Aspects of Medicine

365

311

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“…Ufd1-Npl4 has been linked to mitotic spindle disassembly and chromosome segregation [73,74], although this has been disputed recently [75]. These diverse functions raise the question how substrate specificity of the Cdc48/p97…”

Section: Npl4mentioning

confidence: 99%

UBX domain proteins: major regulators of the AAA ATPase Cdc48/p97

Schuberth¹,

Buchberger

2008

Cell. Mol. Life Sci.

264

275

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Abstract. The highly conserved AAA ATPase Cdc48/ p97 acts on ubiquitylated substrate proteins in cellular processes as diverse as the fusion of homotypic membranes and the degradation of misfolded proteins. The Ubiquitin regulatory X (UBX) domaincontaining proteins constitute the so far largest family of Cdc48/p97 cofactors. UBX proteins are involved in substrate recruitment to Cdc48/p97 and in the temporal and spatial regulation of its activity. In combination with UBX-like proteins and other cofactors, they can assemble into a large variety of Cdc48/p97-cofactor complexes possessing distinct cellular functions. This review gives an overview of the different subfamilies of UBX proteins and their functions, and discusses general principles of Cdc48/p97 regulation by these cofactors.

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The AAA-ATPase p97-Ufd1-Npl4 is required for ERAD but not for spindle disassembly in Xenopus egg extracts

Cited by 29 publications

References 16 publications

p97 Promotes a Conserved Mechanism of Helicase Unloading during DNA Cross-Link Repair

p97 Promotes a Conserved Mechanism of Helicase Unloading during DNA Cross-Link Repair

The proteasomal system

UBX domain proteins: major regulators of the AAA ATPase Cdc48/p97

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