CDC7-independent G1/S transition revealed by targeted protein degradation

Suski, Jan M.; Ratnayeke, Nalin; Braun, Marcin; Zhang, Tian; Strmiska, Vladislav; Michowski, Wojciech; Can, Geylani; Simoneau, Antoine; Snioch, Konrad; Cup, Mikolaj; Sullivan, Caitlin; Wu, Xiumei; Nowacka, Joanna; Branigan, Timothy; Pack, Lindsey R.; DeCaprio, James A.; Geng, Yan; Zou, Lee; Gygi, Steven P.; Walter, Johannes C.; Meyer, Tobias; Siciński, Piotr

doi:10.1038/s41586-022-04698-x

Cited by 45 publications

(45 citation statements)

References 47 publications

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“…Given that PGAM5 regulates mitochondrial dynamics and programmed cell death [70], it is worth exploring whether this interaction highlights non-canonical roles of SLX4 complexes in mitochondrial biology. On the other hand, CDC7 is a highly conserved serine-threonine kinase that promotes DNA replication by activating origins of replication and, thus, has a key role in promoting the G1/S phase progression [71, 72]. Whether CDC7 phosphorylates SLX4 is a question for future research.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Interactome Mapping of the DNA Repair Scaffold SLX4 using Proximity Labeling and Affinity Purification

Aprosoff

Dyakov

Cheung

et al. 2022

Preprint

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The DNA repair scaffold SLX4 has pivotal roles in cellular processes that maintain genome stability, most notably homologous recombination. Germline mutations in SLX4 are associated with Fanconi anemia, a disease characterized by chromosome instability and cancer susceptibility. The role of mammalian SLX4 in homologous recombination depends critically on binding and activating structure-selective endonucleases, namely SLX1, MUS81-EME1, and XPF-ERCC1. Increasing evidence indicates that cells rely on distinct SLX4-dependent complexes to remove DNA lesions in specific regions of the genome. Despite our understanding of SLX4 as a scaffold for DNA repair proteins, a detailed repertoire of SLX4 interactors has never been reported. Here, we provide the first comprehensive map of the human SLX4 interactome using proximity-dependent biotin identification (BioID) and affinity purification coupled to mass spectrometry (AP-MS). We identified 237 high-confidence interactors, of which the vast majority represent novel SLX4 binding proteins. Network analysis of these hits revealed pathways with known involvement of SLX4, such as DNA repair, and novel or emerging pathways of interest, including RNA metabolism and chromatin remodeling. In summary, the comprehensive SLX4 interactome we report here provides a deeper understanding of how SLX4 functions in DNA repair while revealing new cellular processes that may involve SLX4.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Interactome Mapping of the DNA Repair Scaffold SLX4 using Proximity Labeling and Affinity Purification

Aprosoff

Dyakov

Cheung

et al. 2022

Preprint

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“…A recent paper directly demonstrates that CDK1 activity is also involved in promoting replication origin firing in mammalian cells, as previously seen in Xenopus [88]. Using a chemical genetic approach, Suski et al [95] found that specific inhibition of CDK1 eliminated a subset of phosphorylations on the replicative helicase subunit MCM2, and reduced the number of replication origins in asynchronous ES cells. Furthermore, most mammalian cell types could still cycle, albeit more slowly, in the absence of CDC7, another conserved kinase previously thought to be essential for triggering the S-phase by phosphorylating MCM proteins.…”

Section: Redundant Cdk-mediated Control Of S-phase Onsetmentioning

confidence: 71%

“…In both Xenopus embryonic cell cycles [106] and human somatic cell cycles [107], appending a nuclear localization signal to cyclin B1 restores efficient DNA replication upon the loss of cyclins E or A, respectively. Furthermore, in the presence of CDK2, CDK1 associates only with cyclin B during early stages of the cell cycle, but not with cyclins E or A, and low levels of cyclin B1 are detected in the nucleus [95].…”

Section: Specific Cdk-cyclin Complexes Are Not Essential For Entry In...mentioning

confidence: 96%

Explaining Redundancy in CDK-Mediated Control of the Cell Cycle: Unifying the Continuum and Quantitative Models

Fisher

Krasińska

2022

Cells

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In eukaryotes, cyclin-dependent kinases (CDKs) are required for the onset of DNA replication and mitosis, and distinct CDK–cyclin complexes are activated sequentially throughout the cell cycle. It is widely thought that specific complexes are required to traverse a point of commitment to the cell cycle in G1, and to promote S-phase and mitosis, respectively. Thus, according to a popular model that has dominated the field for decades, the inherent specificity of distinct CDK–cyclin complexes for different substrates at each phase of the cell cycle generates the correct order and timing of events. However, the results from the knockouts of genes encoding cyclins and CDKs do not support this model. An alternative “quantitative” model, validated by much recent work, suggests that it is the overall level of CDK activity (with the opposing input of phosphatases) that determines the timing and order of S-phase and mitosis. We take this model further by suggesting that the subdivision of the cell cycle into discrete phases (G0, G1, S, G2, and M) is outdated and problematic. Instead, we revive the “continuum” model of the cell cycle and propose that a combination with the quantitative model better defines a conceptual framework for understanding cell cycle control.

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“…It should be noted that a recent study describes the growth of both human and murine cells in which DDK activity is either inhibited or depleted [ 67 ]. Murine cells harbouring an ‘analogue sensitive’ mutation in the Cdc7 ATP binding pocket showed retarded proliferation but did not arrest following treatment with an ATP analogue; furthermore, following either chemically- or genetically-mediated degradation of either Cdc7 or Dbf4 (a requirement for Drf1 was not tested), both human and murine cells can maintain proliferation although changes to S phase length were apparent.…”

Section: Rif1: Antagonising Ddk-mediated Mcm4 Phosphorylationmentioning

confidence: 99%

DDK: The Outsourced Kinase of Chromosome Maintenance

Gillespie

Blow

2022

Biology

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The maintenance of genomic stability during the mitotic cell-cycle not only demands that the DNA is duplicated and repaired with high fidelity, but that following DNA replication the chromatin composition is perpetuated and that the duplicated chromatids remain tethered until their anaphase segregation. The coordination of these processes during S phase is achieved by both cyclin-dependent kinase, CDK, and Dbf4-dependent kinase, DDK. CDK orchestrates the activation of DDK at the G1-to-S transition, acting as the ‘global’ regulator of S phase and cell-cycle progression, whilst ‘local’ control of the initiation of DNA replication and repair and their coordination with the re-formation of local chromatin environments and the establishment of chromatid cohesion are delegated to DDK. Here, we discuss the regulation and the multiple roles of DDK in ensuring chromosome maintenance. Regulation of replication initiation by DDK has long been known to involve phosphorylation of MCM2-7 subunits, but more recent results have indicated that Treslin:MTBP might also be important substrates. Molecular mechanisms by which DDK regulates replisome stability and replicated chromatid cohesion are less well understood, though important new insights have been reported recently. We discuss how the ‘outsourcing’ of activities required for chromosome maintenance to DDK allows CDK to maintain outright control of S phase progression and the cell-cycle phase transitions whilst permitting ongoing chromatin replication and cohesion establishment to be completed and achieved faithfully.

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CDC7-independent G1/S transition revealed by targeted protein degradation

Cited by 45 publications

References 47 publications

Comprehensive Interactome Mapping of the DNA Repair Scaffold SLX4 using Proximity Labeling and Affinity Purification

Comprehensive Interactome Mapping of the DNA Repair Scaffold SLX4 using Proximity Labeling and Affinity Purification

Explaining Redundancy in CDK-Mediated Control of the Cell Cycle: Unifying the Continuum and Quantitative Models

DDK: The Outsourced Kinase of Chromosome Maintenance

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