CUL4B-deficiency in humans: Understanding the clinical consequences of impaired Cullin 4-RING E3 ubiquitin ligase function

Kerzendorfer, Claudia; Hart, Lesley; Colnaghi, Rita; Carpenter, Gillian; Alcantara, Diana; Outwin, Emily; Carr, Antony; O’Driscoll, Mark

doi:10.1016/j.mad.2011.02.003

Cited by 37 publications

(34 citation statements)

References 69 publications

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“…Existence of a human disorder resulting from CUL4B deficiency suggests that CUL4A cannot fully compensate for defective CUL4B activity. Deletions of the CUL4B gene in patients [the present case and Ref (6)] are probably to represent functional null mutations of CUL4B , as also supported by qRT‐PCR analyses and protein expression studies (3). Similarly, most of the intragenic CUL4B mutations result in significantly reduced protein expression, possibly as a result of nonsense mediated RNA decay in the case of truncating mutations (8).…”

Section: Clinical Features In Patients With Mutations In Cul4bsupporting

confidence: 70%

“…Vertebrates have two highly identical Cullin 4‐RING E3 ligase (CRL4) genes, CUL4A and CUL4B , which encode subunits of E3‐ubiquitin ligases implicated in processes such as nucleotide excision repair, regulation gene expression and controlling DNA replication licensing (3). The functional distinction between these two proteins is not clear, but CUL4B mutations give rise to a syndromal form of MR (1, 2), while no human disorder associated with CUL4A mutations have been described to date.…”

Section: Clinical Features In Patients With Mutations In Cul4bmentioning

confidence: 99%

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Deletion of CUL4B leads to concordant phenotype in a monozygotic twin pair

Ravn

Lindquist

Nielsen³

et al. 2012

Clinical Genetics

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Section: Clinical Features In Patients With Mutations In Cul4bsupporting

confidence: 70%

Section: Clinical Features In Patients With Mutations In Cul4bmentioning

confidence: 99%

Deletion of CUL4B leads to concordant phenotype in a monozygotic twin pair

Ravn

Lindquist

Nielsen³

et al. 2012

Clinical Genetics

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“…Both of the groups investigating sperm development in Cul4a -deficient mice found that primary spermatocytes could not resolve dsDNA breaks and underwent extensive apoptosis (Kopanja et al, 2011; Yin et al, 2011). Similarly, CUL4B -deficient human males typically exhibit hypogonadism (see below for more information on clinical relevance) (Kerzendorfer et al, 2011). …”

Section: Cellular and Developmental Functions Of Crl4 Ligasesmentioning

confidence: 99%

Distinct and overlapping functions of the cullin E3 ligase scaffolding proteins CUL4A and CUL4B

Hannah

Zhou

2015

Gene

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The cullin 4 subfamily of genes includes CUL4A and CUL4B, which share a mostly identical amino acid sequence aside from the elongated N-terminal region in CUL4B. Both act as scaffolding proteins for modular cullin RING ligase 4 (CRL4) complexes which promote the ubiquitination of a variety of substrates. CRL4 function is vital to cells as loss of both genes or their shared substrate adaptor protein DDB1 halts proliferation and eventually leads to cell death. Due to their high structural similarity, CUL4A and CUL4B share a substantial overlap in function. However, in some cases, differences in subcellular localization, spatiotemporal expression patterns and stress-inducibility preclude functional compensation. In this review, we highlight the most essential functions of the CUL4 genes in: DNA repair and replication, chromatin-remodeling, cell cycle regulation, embryogenesis, hematopoiesis and spermatogenesis. CUL4 genes are also clinically relevant as dysregulation can contribute to the onset of cancer and CRL4 complexes are often hijacked by certain viruses to promote viral replication and survival. Also, mutations in CUL4B have been implicated in a subset of patients suffering from syndromic X-linked intellectual disability (AKA mental retardation). Interestingly, the antitumor effects of immunomodulatory drugs are caused by their binding to the CRL4CRBN complex and re-directing the E3 ligase towards the Ikaros transcription factors IKZF1 and IKZF3. Because of their influence over key cellular functions and relevance to human disease, CRL4s are considered promising targets for therapeutic intervention.

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“…20,21). Cullin 4 is evolutionarily conserved from yeast to humans with invertebrates containing a single gene and vertebrates two genes as a consequence of gene duplication.…”

mentioning

confidence: 99%

Cullin 4B Is Recruited to Tristetraprolin-Containing Messenger Ribonucleoproteins and Regulates TNF-α mRNA Polysome Loading

Pfeiffer

Brooks

2012

The Journal of Immunology

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TNF-α is a central mediator of inflammation and critical for host response to infection and injury. TNF-α biosynthesis is controlled by transcriptional and posttranscriptional mechanisms allowing for rapid, transient production. Tristetraprolin (TTP) is an AU-rich element binding protein that regulates the stability of the TNF-α mRNA. Using a screen to identify TTP-interacting proteins, we identified Cullin 4B (Cul4B), a scaffolding component of the Cullin ring finger ligase family of ubiquitin E3 ligases. Short hairpin RNA knockdown of Cul4B results in a significant reduction in TNF-α protein and mRNA in LPS-stimulated mouse macrophage RAW264.7 cells as well as a reduction in TTP protein. TNF-α message t1/2 was reduced from 69 to 33 min in LPS-stimulated cells. TNF-3′ untranslated region luciferase assays utilizing wild-type and mutant TTP-AA (S52A, S178A) indicate that TTP function is enhanced in Cul4B short hairpin RNA cells. Importantly, the fold induction of TNF-α mRNA polysome loading in response to LPS stimulation is reduced by Cul4B knockdown. Cul4B is present on the polysomes and colocalizes with TTP to exosomes and processing bodies, which are sites of mRNA decay. We conclude that Cul4B licenses the TTP-containing TNF-α messenger ribonucleoprotein for loading onto polysomes, and reduction of Cul4B expression shunts the messenger ribonucleoproteins into the degradative pathway.

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CUL4B-deficiency in humans: Understanding the clinical consequences of impaired Cullin 4-RING E3 ubiquitin ligase function

Cited by 37 publications

References 69 publications

Deletion of CUL4B leads to concordant phenotype in a monozygotic twin pair

Deletion of CUL4B leads to concordant phenotype in a monozygotic twin pair

Distinct and overlapping functions of the cullin E3 ligase scaffolding proteins CUL4A and CUL4B

Cullin 4B Is Recruited to Tristetraprolin-Containing Messenger Ribonucleoproteins and Regulates TNF-α mRNA Polysome Loading

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