Polyubiquitylation drives replisome disassembly at the termination of DNA replication

Moreno, Sara Priego; Bailey, Rachael; Campion, Nicholas J.; Herron, Suzanne; Gambus, Agnieszka

doi:10.1126/science.1253585

Cited by 172 publications

(177 citation statements)

References 40 publications

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“…Many studies have shown the value of MCM family proteins as diagnostic and prognostic markers in many tumor types (26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45) and we hereby report that, in PAs, MCM7 may be a possible marker of pituitary tumor aggressiveness.…”

Section: Discussionmentioning

confidence: 88%

“…These proteins display weak helicase activity, and are involved in several aspects of transcriptional control (24). MCM protein activity is modulated by various molecules, including cyclins, growth factors, retinoblastoma tumor suppressor protein, p21, p27, and pTEN and they are regulated by a range of molecular pathways, such as phosphorylation, ubiquitylation, and acetylation (19,22,24,25,26,27).…”

Section: Introductionmentioning

confidence: 99%

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Minichromosome maintenance protein 7 as prognostic marker of tumor aggressiveness in pituitary adenoma patients

Coli

Sylvia

Fadda

et al. 2016

European Journal of Endocrinology

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Background: Ki-67 labeling index (LI) is currently regarded as a useful prognostic marker of pituitary adenoma (PA) clinical behavior, although its relevance as a reliable clinical indicator is far from being universally accepted, since both validations and criticisms are found in the literature. Minichromosome maintenance 7 (MCM7), a cell-cycle regulator protein, has been recently proposed as a marker of tumor aggressiveness in tumors from many sites, including the CNS. Therefore, we evaluated MCM7, in comparison to Ki-67, as a potential marker of clinical outcome in PA. Design and methods: In this single-institution retrospective study, 97 patients with PA (23 ACTH, 12 GH, 29 PRL, 10 FSH/LH, and 23 non-secreting adenomas) were recruited and the prognostic value of both MCM7 and Ki-67 was evaluated by immunohistochemical techniques. In addition, p53 nuclear expression and mitotic index were also evaluated. Results: Twenty-six of the 97 PA patients recurred during the follow-up period. Cox's regression analysis showed that high nuclear expression of MCM7 LI, unlike Ki-67 LI, was directly associated with a higher (7.7-fold) risk of recurrence/progression. Kaplan-Meier analysis of recurrence/progression-free survival curves revealed that patients with high MCM7 LI (R15%) had a shorter recurrence/progression-free survival than those with low MCM7 LI (!15%). Moreover, among patients with invasive tumors, high MCM7 LI identified those with the highest risk of recurrence/progression. Conclusions: Data from this study suggest that MCM7 is a prognostic marker of clinical outcome in PA patients, more reliable and informative than Ki-67.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Minichromosome maintenance protein 7 as prognostic marker of tumor aggressiveness in pituitary adenoma patients

Coli

Sylvia

Fadda

et al. 2016

European Journal of Endocrinology

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“…During replication termination, CMG unloading was shown to involve polyubiquitylation of MCM7 by using K48-linked chains (33,34). To compare p97-mediated helicase unloading during ICL repair and replication termination, pICL or an undamaged control plasmid (pControl) was allowed to replicate in extract.…”

Section: Resultsmentioning

confidence: 99%

“…3D, 4, and 5B) (33,34). Although K48 linkages play a prominent role in protein turnover, proteasomal degradation was not required for helicase unloading (Fig.…”

Section: Discussionmentioning

confidence: 99%

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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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A SUMO and ubiquitin code coordinates protein traffic at replication factories

Lecona

Fernández-Capetillo

2016

BioEssays

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Post-translational modifications regulate each step of DNA replication to ensure the faithful transmission of genetic information. In this context, we recently showed that deubiquitination of SUMO2/3 and SUMOylated proteins by USP7 helps to create a SUMO-rich and ubiquitin-low environment around replisomes that is necessary to maintain the activity of replication forks and for new origin firing. We propose that a two-flag system mediates the collective concentration of factors at sites of DNA replication, whereby SUMO and Ubiquitinated-SUMO would constitute "stay" or "go" signals respectively for replisome and accessory factors. We here discuss the findings that led to this model, which have implications for the potential use of USP7 inhibitors as anticancer agents.

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Polyubiquitylation drives replisome disassembly at the termination of DNA replication

Cited by 172 publications

References 40 publications

Minichromosome maintenance protein 7 as prognostic marker of tumor aggressiveness in pituitary adenoma patients

Minichromosome maintenance protein 7 as prognostic marker of tumor aggressiveness in pituitary adenoma patients

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

A SUMO and ubiquitin code coordinates protein traffic at replication factories

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