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

Jang, Sang‐Min; Nathans, Jenny F.; Fu, Haiqing; Redon, Christophe E.; Jenkins, Lisa M. Miller; Thakur, Bhushan; Baris, Adrian; Gross, Jacob M.; O'Neill, Michael C.; Indig, Fred E.; Cappell, Steven D.; Aladjem, Mirit I.

doi:10.1038/s41467-019-13808-9

Cited by 23 publications

(29 citation statements)

References 70 publications

(96 reference statements)

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“…DCAF14 (or PHIP, RepID) is one of 18 known CRL4 substrate receptors ( Jin et al, 2006 ). Human DCAF14 functions in mitogenesis ( Farhang-Fallah et al, 2002 ; Podcheko et al, 2007 ), replication origin initiation ( Zhang et al, 2016 ), and regulation of the spindle assembly checkpoint ( Jang et al, 2020 ). DCAF14 is also a prognostic biomarker for metastatic melanoma ( De Semir et al, 2012 ), and deleterious de novo mutations in DCAF14 are associated with developmental abnormalities ( Webster et al, 2016 ; Craddock et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

DCAF14 promotes stalled fork stability to maintain genome integrity

et al. 2021

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SUMMARY Replication stress response ensures impediments to DNA replication do not compromise replication fork stability and genome integrity. In a process termed replication fork protection, newly synthesized DNA at stalled replication forks is stabilized and protected from nuclease-mediated degradation. We report the identification of DDB1- and CUL4-associated factor 14 (DCAF14), a substrate receptor for Cullin4-RING E3 ligase (CRL4) complex, integral in stabilizing stalled replication forks. DCAF14 localizes rapidly to stalled forks and promotes genome integrity by preventing fork collapse into double-strand breaks (DSBs). Importantly, CRL4 DCAF14 mediates stalled fork protection in a RAD51-dependent manner to protect nascent DNA from MRE11 and DNA2 nucleases. Thus, our study shows replication stress response functions of DCAF14 in genome maintenance.

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Section: Introductionmentioning

confidence: 99%

DCAF14 promotes stalled fork stability to maintain genome integrity

et al. 2021

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“…Accumulation of other CRL4 substrates such as the histone methyltransferase SET8 or the CDK inhibitor p21, which is required for proper S-phase progression, prevention of spontaneous DNA damage and activation of the G2/M checkpoint, can also generate DSB (Jorgensen, Elvers et al 2007;Abbas, Sivaprasad et al 2008;Huen, Sy et al 2008;Kim, Starostina et al 2008;Liu, Lee et al 2009;Tardat, Brustel et al 2010). The BUB3-mediated delay in the metaphase-anaphase transition, followed by abnormal chromosomal segregation in RepID-deficient cells are also possibly associated with the occurrence of DNA damage foci (Janssen, van der Burg et al 2011, Jang, Nathans et al 2020a. RepID's functional domains mediate its interaction with chromatin and might underlie its role in regulating the DNA damage response.…”

Section: Discussionmentioning

confidence: 99%

RepID-deficient cancer cells are sensitized to a drug targeting p97/VCP segregase

Jang

Redon

et al. 2021

Mol. Cell. Toxicol.

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Background The p97/valosin-containing protein (VCP) complex is a crucial factor for the segregation of ubiquitinated proteins in the DNA damage response and repair pathway. Objective We investigated whether blocking the p97/VCP function can inhibit the proliferation of RepID-deficient cancer cells using immunofluorescence, clonogenic survival assay, fluorescence-activated cell sorting, and immunoblotting. Result p97/VCP was recruited to chromatin and colocalized with DNA double-strand breaks in RepID-deficient cancer cells that undergo spontaneous DNA damage. Inhibition of p97/VCP induced death of RepID-depleted cancer cells. This study highlights the potential of targeting p97/VCP complex as an anticancer therapeutic approach. Conclusion Our results show that RepID is required to prevent excessive DNA damage at the endogenous levels. Localization of p97/VCP to DSB sites was induced based on spontaneous DNA damage in RepID-depleted cancer cells. Anticancer drugs targeting p97/VCP may be highly potent in RepID-deficient cells. Therefore, we suggest that p97/VCP inhibitors synergize with RepID depletion to kill cancer cells.

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“…Our previous study has also illustrated that CRL4 Cul4/DDB1 E3 ubiquitin ligase regulates ovarian cancer drug resistance by targeting the anti-apoptotic protein BIRC3 [78] . Jang et al [79] further showed that deficiencies in RepID, CRL4, or RBBP7 delayed mitotic exit, increased genomic instability, and enhanced sensitivity of ovarian cacner cells to paclitaxel.…”

Section: Cullin-ring E3 Ubiquitin Ligasesmentioning

confidence: 99%

The emerging roles of E3 ubiquitin ligases in ovarian cancer chemoresistance

Meng¹,

Qiu²,

Zhang³

et al. 2021

CDR

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Epithelial cancer of the ovary exhibits the highest mortality rate of all gynecological malignancies in women today, since the disease is often diagnosed in advanced stages. While the treatment of cancer with specific chemical agents or drugs is the favored treatment regimen, chemotherapy resistance greatly impedes successful ovarian cancer chemotherapy. Thus, chemoresistance becomes one of the most critical clinical issues confronted when treating patients with ovarian cancer. Convincing evidence hints that dysregulation of E3 ubiquitin ligases is a key factor in the development and maintenance of ovarian cancer chemoresistance. This review outlines recent advancement in our understanding of the emerging roles of E3 ubiquitin ligases in ovarian cancer chemoresistance. We also highlight currently available inhibitors targeting E3 ligase activities and discuss their potential for clinical applications in treating chemoresistant ovarian cancer patients.

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

Cited by 23 publications

References 70 publications

DCAF14 promotes stalled fork stability to maintain genome integrity

DCAF14 promotes stalled fork stability to maintain genome integrity

RepID-deficient cancer cells are sensitized to a drug targeting p97/VCP segregase

The emerging roles of E3 ubiquitin ligases in ovarian cancer chemoresistance

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