Chromatin-Bound Cullin-Ring Ligases: Regulatory Roles in DNA Replication and Potential Targeting for Cancer Therapy

Jang, Sang‐Min; Redon, Christophe E.; Aladjem, Mirit I.

doi:10.3389/fmolb.2018.00019

Cited by 42 publications

(43 citation statements)

References 222 publications

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“…The above observations suggest that BUB3 is a substrate of CRL4 and that its interaction with CRL4 facilitates its ubiquitination and degradation during mitosis. Since we observed that BUB3 levels were stable, and even increased, during interphase, we sought to identify a mechanism that would prevent BUB3 degradation during interphase despite the presence of active, chromatinbound CRL4 5,14 . As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Transitions between these major events are orchestrated by posttranslational modifications to ensure the preservation of genomic information [1][2][3][4] . Ubiquitin ligases regulate cell cycle progression by mediating the timely degradation of effector proteins [5][6][7][8] . Cullin-RING ubiquitin ligase complex 4 (CRL4) associates with a diverse array of substrates through a series of WD motif containing substrate receptors known as DDB1-CUL4-associated factors (DCAFs) 9 .…”

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confidence: 99%

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The RepID–CRL4 ubiquitin ligase complex regulates metaphase to anaphase transition via BUB3 degradation

Jang

Nathans

et al. 2020

Nat Commun

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The spindle assembly checkpoint (SAC) prevents premature chromosome segregation by inactivating the anaphase promoting complex/cyclosome (APC/C) until all chromosomes are properly attached to mitotic spindles. Here we identify a role for Cullin-RING ubiquitin ligase complex 4 (CRL4), known for modulating DNA replication, as a crucial mitotic regulator that triggers the termination of the SAC and enables chromosome segregation. CRL4 is recruited to chromatin by the replication origin binding protein RepID/DCAF14/PHIP. During mitosis, CRL4 dissociates from RepID and replaces it with RB Binding Protein 7 (RBBP7), which ubiquitinates the SAC mediator BUB3 to enable mitotic exit. During interphase, BUB3 is protected from CRL4-mediated degradation by associating with promyelocytic leukemia (PML) nuclear bodies, ensuring its availability upon mitotic onset. Deficiencies in RepID, CRL4 or RBBP7 delay mitotic exit, increase genomic instability and enhance sensitivity to paclitaxel, a microtubule stabilizer and anti-tumor drug.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

The RepID–CRL4 ubiquitin ligase complex regulates metaphase to anaphase transition via BUB3 degradation

Jang

Nathans

et al. 2020

Nat Commun

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“…Both high LOXL2 levels and its perinuclear localization are associated with poor outcome and lower survival rates of patients with breast cancer (Ahn et al, 2013;Moreno-Bueno et al, 2011). Furthermore, both RUVBL2 and CRL4B complex are also known to play important roles in cancer biology (Grigoletto et al, 2011;Grigoletto et al, 2013;Jang et al, 2018;Mao and Houry, 2017).…”

Section: Discussionmentioning

confidence: 99%

Maintaining oxidized H3 in heterochromatin is required for the oncogenic capacity of triple-negative breast cancer cells

Serra-Bardenys¹,

Tian²,

Querol³

et al. 2020

Preprint

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The histone modification of H3 oxidized at lysine 4 (H3K4ox) is catalyzed by lysyl oxidase-like 2 (LOXL2) and is enriched in heterochromatin in triple-negative breast cancer (TNBC) cells. Although H3K4ox has been linked to the maintenance of compacted chromatin, the molecular mechanism underlying this maintenance is unknown. Here we show that H3K4ox is read by the CRL4B complex, leading to the ubiquitination of histone H2A through the E3 ligase RBX1. Finally, interactions between RUVBL1/2 and LOXL2 are involved in the incorporation of the histone variant H2A.Z, which plays an essential role in the mechanism controlling the dynamics of oxidized H3. Maintenance of H3K4ox in chromatin is essential for heterochromatin properties, and disruption of any of the members involved in this pathway blocks the oncogenic properties of TNBC cells. 2018). H3K9me2/3 are recognized by heterochromatin protein 1 (HP1), which has a major role in ensuring heterochromatin compaction, spreading, and inheritance (Bannister et al., 2001).Heterochromatin is not only essential for the maintenance of genome stability but can also directly affect genome integrity, through changes in its highly dynamic structure (Janssen et al., 2018).Therefore, there is a pressing need to improve our understanding of the role of heterochromatin, and the mechanisms by which it is maintained at a mechanistic level. To address this, we employed, unbiased proteomic assays to identify LOXL2 partners, as well as H3K4ox readers. We found that LOXL2 interacts with members of the SRCAP and TIP60 complexes, and that H3K4ox is read by the CRL4B complex. Both of these complexes are involved in loading the histone H2A variant, H2A.Z, into chromatin (Buschbeck and Hake, 2017; Morrison and Shen, 2009). We also discovered that the CRL4B complex is involved in the ubiquitination of H2A by RBX1, that is required for the exchange of the H2A variant, H2A.Z. Notably, both in vitro and in vivo, these series of events are necessary to maintain condensed chromatin in triple-negative breast cancer (TNBC) cells. Knocking down any component of this pathway resulted in inhibition of oncogenic and metastatic traits in TNBC cells, including proliferation, migration, invasion, and in vivo tumor formation capacity. Thus, we propose the existence of a direct link between oxidation of H3, chromatin condensation, and tumorigenic capacities, and argue that any of the components described in the H3K4ox pathway could potentially be targetable factors for treating TNBC. RESULTS The Roles of LOXL2, RUVBL2, and H2A.Z in Chromatin CondensationWe revisited a tandem-affinity purification approach previously published by our lab to identify putative LOXL2 interactors that might be involved in the maintenance or generation of compacted chromatin induced by H3K4ox-LOXL2 (Cebria-Costa et al., 2019;Herranz et al., 2016). Analysis of the new list of interactors showed the presence of two AAA+ ATPases (RUVBL1 and RUVBL2), DMAP1 and BAF53, all of which are members of the SRCAP and TIP60 complexes ( Figure 1A a...

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“…CRLs are a very large family of multisubunit E3 ubiquitin ligases containing 1 of 8 cullin scaffolds (Bulatov and Ciulli, 2015;Jang et al, 2018). CRL4s are composed of cullin4(A/B), DDB1 adaptor, RBX1 E2-binding RING finger, and one of many substrate-recruiting receptors (Hannah and Zhou, 2015).…”

Section: Cullin-ring Ligase (Crl) 4 Cdt2mentioning

confidence: 99%

The Identification of Potential Therapeutic Targets for Cutaneous Squamous Cell Carcinoma

McHugh

Fernandes

Chinner

et al. 2020

Journal of Investigative Dermatology

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We performed a small interfering RNA screen to identify targets for cutaneous squamous cell carcinoma (cSCC) therapy in the ubiquitin/ubiquitin-like system. We provide evidence for selective anti-cSCC activity of knockdown of the E3 ubiquitin ligase MARCH4, the ATPase p97/VCP, the deubiquitinating enzyme USP8, the cullin-RING ligase (CRL) 4 substrate receptor CDT2/DTL, and components of the anaphase-promoting complex/ cyclosome (APC/C). Specifically attenuating CRL4 CDT2 by CDT2 knockdown can be more potent in killing cSCC cells than targeting CRLs or CRL4s in general by RBX1 or DDB1 depletion. Suppression of the APC/C or forced APC/C activation by targeting its repressor EMI1 are both potential therapeutic approaches. We observed that cSCC cells can be selectively killed by small-molecule inhibitors of USP8 (DUBs-IN-3/compound 22c) and the NEDD8 E1 activating enzyme/CRLs (MLN4924/pevonedistat). A substantial proportion of cSCC cell lines are very highly MLN4924-sensitive. Pathways that respond to defects in proteostasis are involved in the anti-cSCC activity of p97 suppression. Targeting USP8 can reduce the expression of growth factor receptors that participate in cSCC development. EMI1 and CDT2 depletion can selectively cause DNA re-replication and DNA damage in cSCC cells.

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Chromatin-Bound Cullin-Ring Ligases: Regulatory Roles in DNA Replication and Potential Targeting for Cancer Therapy

Cited by 42 publications

References 222 publications

The RepID–CRL4 ubiquitin ligase complex regulates metaphase to anaphase transition via BUB3 degradation

The RepID–CRL4 ubiquitin ligase complex regulates metaphase to anaphase transition via BUB3 degradation

Maintaining oxidized H3 in heterochromatin is required for the oncogenic capacity of triple-negative breast cancer cells

The Identification of Potential Therapeutic Targets for Cutaneous Squamous Cell Carcinoma

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