RNF4-mediated polyubiquitination regulates the Fanconi anemia/BRCA pathway

Xie, Jenny; Kim, Hyungjin; Moreau, Lisa A.; Puhalla, Shannon; Garber, Judy E.; Abo, Muthana Al; Takeda, Shunichi; D’Andrea, Alan D.

doi:10.1172/jci79325

Cited by 40 publications

(43 citation statements)

References 51 publications

(70 reference statements)

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“…To standardize our own assays, we engineered patient-derived GM6914 cells (which express no functional FANCA protein) to express a severe (T724P) or moderate (I939S) FANCA mutant. Both cell lines behaved as previously reported (Xie et al, 2015; Yagasaki et al, 2004) (Figures S2K–L). Of two FANCA clinical mutants previously characterized as mild, one (D598N) showed no increase in chaperone binding, while the second (F868V) showed a comparable increase in HSP90 and HSP70 binding (Figure S2J; Table S2C).…”

Section: Resultssupporting

confidence: 88%

HSP90 Shapes the Consequences of Human Genetic Variation

Karras

Sahni

et al. 2017

Cell

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Summary HSP90 acts as a protein-folding buffer that shapes the manifestations of genetic variation in model organisms. Whether HSP90 influences the consequences of mutations in humans, potentially modifying the clinical course of genetic diseases, remains unknown. Mining data for >1,500 disease-causing mutants, we found strong correlation between reduced phenotypic severity and a dominant (HSP90≥HSP70) increase in mutant engagement by HSP90. Examining the cancer predisposition syndrome Fanconi Anemia in depth revealed that mutant FANCA proteins engaged predominantly by HSP70 had severely compromised function. In contrast, the function of less severe mutants was preserved by a dominant increase in HSP90 binding. Reducing HSP90’s buffering capacity with inhibitors or febrile temperatures destabilized HSP90-buffered mutants, exacerbating FA-related chemosensitivities. Strikingly, a compensatory FANCA somatic mutation from an “experiment of nature” in monozygotic twins both prevented anemia and reduced HSP90 binding. These findings provide one plausible mechanism for the variable expressivity and environmental sensitivity of genetic diseases.

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Section: Resultssupporting

confidence: 88%

HSP90 Shapes the Consequences of Human Genetic Variation

Karras

Sahni

et al. 2017

Cell

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117

113

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“…A NOA gene encoding a component of the UPS is RNF4, a RING-type E3 ubiquitin ligase. In its canonical function, RNF4 targets polysumoylated proteins (including PML, PEA3, CENPI, EPAS1, and PARP1) for degradation, controlling chromosome alignment and spindle assembly (325). This function is not directly related to cancer development, and RNF4 is usually not altered (neither genetically nor epigenetically) in cancer.…”

Section: B-trcpmentioning

confidence: 99%

Degrons in cancer

et al. 2017

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Degrons are the elements that are used by E3 ubiquitin ligases to target proteins for degradation. Most degrons are short linear motifs embedded within the sequences of modular proteins. As regulatory sites for protein abundance, they are important for many different cellular processes, such as progression through the cell cycle and monitoring cellular hypoxia. Degrons enable the elimination of proteins that are no longer required, preventing their possible dysfunction. Although the human genome encodes~600 E3 ubiquitin ligases, only a fraction of these enzymes have well-defined target degrons. Thus, for most cellular proteins, the destruction mechanisms are poorly understood. This is important for many diseases, especially for cancer, a disease that involves the enhanced expression of oncogenes and the persistence of encoded oncoproteins coupled with reduced abundance of tumor suppressors. Lossof-function mutations occur in the degrons of several oncoproteins, such as the transcription factors MYC and NRF2, and in various mitogenic receptors, such as NOTCH1 and several receptor tyrosine kinases. Mutations eliminating the function of the b-catenin degron are found in many cancers and are considered one of the most abundant mutations driving carcinogenesis. In this Review, we describe the current knowledge of degrons in cancer and suggest that increased research on the "dark degrome" (unknown degron-E3 relationships) would enhance progress in cancer research.

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“…Many components of the FA/BCRA pathway are modified by SUMO and Ub to promote the DNA repair process . Recently, a role for RNF4 was implicated in regulating the FA pathway . Xie and colleagues identified an FA patient with a point mutation in FANCA, which encodes a mutant FANCA protein (FANCA I939S ).…”

Section: Rnf4—a Novel Regulator Of Dna Damage Response and Genomic Inmentioning

confidence: 99%

RNF4—A Paradigm for SUMOylation‐Mediated Ubiquitination

Kumar

Sabapathy

2019

Proteomics

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Covalent modifications by Small Ubiquitin‐like MOdifier (SUMO) and ubiquitin conjugation are now recognized as independent posttranslational modifications (PTMs) employed by cells to reversibly regulate cellular signaling. SUMOylation in particular has emerged as a crucial cellular mechanism involved in multiple pathologies, including cancers, cardiovascular diseases, immunological and neurological disorders, as well as aging. Convergence of these two PTMs result in the ubiquitination of SUMOylated proteins, adding complexity in the modulation of protein functions. The SUMO‐Targeted Ubiquitin Ligases (STUbL) mediate this process, and RNF4, the mammalian STUbL, has been at the forefront in the understanding of this phenomenon. It has been shown to play important roles in a variety of cellular events, ranging from the maintenance of genomic integrity and hence, oncogenesis, to a role in development. Recent identification of direct and indirect RNF4 targets has revealed that the SUMOylation machinery is in itself targeted by RNF4, highlighting the complex nature of the signaling circuitry tightly regulating these processes. This review will touch upon both SUMOylation and ubiquitination, and will focus on how RNF4, which is at the heart of both these PTMs, modulates cellular signaling and promotes protein degradation. Moreover, the potential of therapeutically targeting RNF4 to improve cancer treatment is also explored.

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RNF4-mediated polyubiquitination regulates the Fanconi anemia/BRCA pathway

Cited by 40 publications

References 51 publications

HSP90 Shapes the Consequences of Human Genetic Variation

HSP90 Shapes the Consequences of Human Genetic Variation

Degrons in cancer

RNF4—A Paradigm for SUMOylation‐Mediated Ubiquitination

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