Solution Structure of RING Finger-like Domain of Retinoblastoma-binding Protein-6 (RBBP6) Suggests It Functions as a U-box

Kappo, M.A.; Ab, Eiso; Hassem, Faqeer; Atkinson, R. Andrew; Faro, Andrew; Muleya, Victor; Mulaudzi, Takalani; Poole, John O.; McKenzie, Jean M.; Chibi, Moredreck; Moolman-Smook, Joanna C.; Rees, D. J. G.; Pugh, D.J.R.

doi:10.1074/jbc.m110.217059

Cited by 16 publications

(16 citation statements)

References 60 publications

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“…Structural representations and models were generated using PyMol (Schrödinger). Similarly the RING domain of BARD1 (PDB 1JM7 chain B) was superimposed on the RING domains of BMI1-RING1B (PDB: 2CKL)40, RAD18 (PDB: 2Y43)41, TRIM37 (PDB:3LRQ)42 and RBBP6 (PDB:3ZTG)43 to identify residues similarly located to BARD1-R99.…”

Section: Methodsmentioning

confidence: 99%

Human BRCA1–BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection

Densham

Garvin

Stone

et al. 2016

Nat Struct Mol Biol

248

297

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The opposing activities of 53BP1 and BRCA1 influence pathway choice of DNA double-strand break repair. How BRCA1 counters the inhibitory effect of 53BP1 on DNA resection and homologous recombination is unknown. Here we identify the site of BRCA1-BARD1 required for priming ubiquitin transfer from E2~ubiquitin. We demonstrate that BRCA1-BARD1's ubiquitin ligase activity is required for repositioning 53BP1 on damaged chromatin. We confirm H2A ubiquitylation by BRCA1-BARD1 and show that an H2A-ubiquitin fusion protein promotes DNA resection and repair in BARD1 deficient cells. We show BRCA1-BARD1 function in homologous recombination requires the chromatin remodeler SMARCAD1. SMARCAD1 binding to H2A-ubiquitin, optimal localization to sites of damage and activity in DNA repair requires its ubiquitin-binding CUE domains. SMARCAD1 is required for 53BP1 repositioning and the need for SMARCAD1 in Olaparib or camptothecin resistance is alleviated by 53BP1 loss. Thus BRCA1-BARD1 ligase activity and subsequent SMARCAD1-dependent chromatin remodeling are critical regulators of DNA repair.Introduction.

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Section: Methodsmentioning

confidence: 99%

Human BRCA1–BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection

Densham

Garvin

Stone

et al. 2016

Nat Struct Mol Biol

248

297

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“…The RING finger in the Mpe1 homolog RBBP6 promotes protein dimerization (23), and bringing together two zinc knuckles in an Mpe1 homodimer may be critical for stable RNA interaction. Alternatively, the Mpe1 RING finger could bind RNA directly.…”

Section: Discussionmentioning

confidence: 99%

“…The third Mpe1 domain is a RING finger domain found in some E3 and E4 enzymes (21)(22)(23). RING-type E3 ubiquitin ligases directly interact both with target substrates and with E2 ubiquitinconjugating enzymes, thereby facilitating the transfer of the ubiquitin from E2 to the target protein (24).…”

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confidence: 99%

Efficient mRNA Polyadenylation Requires a Ubiquitin-Like Domain, a Zinc Knuckle, and a RING Finger Domain, All Contained in the Mpe1 Protein

Lee

Moore

2014

Molecular and Cellular Biology

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Almost all eukaryotic mRNAs must be polyadenylated at their 3= ends to function in protein synthesis. This modification occurs via a large nuclear complex that recognizes signal sequences surrounding a poly(A) site on mRNA precursor, cleaves at that site, and adds a poly(A) tail. While the composition of this complex is known, the functions of some subunits remain unclear. One of these is a multidomain protein called Mpe1 in the yeast Saccharomyces cerevisiae and RBBP6 in metazoans. The three conserved domains of Mpe1 are a ubiquitin-like (UBL) domain, a zinc knuckle, and a RING finger domain characteristic of some ubiquitin ligases. We show that mRNA 3=-end processing requires all three domains of Mpe1 and that more than one region of Mpe1 is involved in contact with the cleavage/polyadenylation factor in which Mpe1 resides. Surprisingly, both the zinc knuckle and the RING finger are needed for RNA-binding activity. Consistent with a role for Mpe1 in ubiquitination, mutation of Mpe1 decreases the association of ubiquitin with Pap1, the poly(A) polymerase, and suppressors of mpe1 mutants are linked to ubiquitin ligases. Furthermore, an inhibitor of ubiquitin-mediated interactions blocks cleavage, demonstrating for the first time a direct role for ubiquitination in mRNA 3=-end processing. Polyadenylation is an essential step in the production of functional eukaryotic mRNA that will be efficiently utilized in translation. It is a nuclear processing event that involves the cleavage of mRNA precursor followed by the addition of a poly(A) tail and is carefully coordinated with other events involved in mRNA synthesis and utilization, such as transcription, splicing, assembly of mRNA into ribonucleoprotein complexes, and mRNA export. Many recent studies have also revealed how selection of the cleavage site can globally affect the type of mRNA produced by cells (1-3). Polyadenylation requires a suite of multiple factors whose subunits are conserved across eukaryotic species (4-6). Significant progress has been made in understanding the contributions of each factor to the recognition of the poly(A) site, the execution of the processing steps, and regulation. However, the precise role of each subunit in this complex process and the impact of posttranslational modifications on the regulation of polyadenylation have not been completely defined.In Saccharomyces cerevisiae, the factors needed for mRNA 3=-end processing are the RNA-binding protein Hrp1 and two multisubunit complexes called cleavage/polyadenylation factor (CPF) and cleavage factor IA (CF IA). One poorly characterized but essential subunit of CPF identified more than 10 years ago is Mpe1, which is needed for both processing steps (7). The mammalian Mpe1 homolog, RBBP6, interacts with the tumor suppressor proteins p53 and pRb (8, 9), possibly linking polyadenylation to regulation of cell growth. Even though RBBP6 is found in the mammalian mRNA 3=-end processing complex (10), it has not been shown to function in polyadenylation.Mpe1 is a particularly interesting s...

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“…P2P-R was shown to localize to the nucleolus of interphase cells and the periphery of chromosomes in cells undergoing mitosis [9]. RBBP6 was also recently proposed to be a U-box protein with a role in controlling protein degradation [10].…”

Section: Introductionmentioning

confidence: 99%

The C. elegans Homolog of RBBP6 (RBPL-1) Regulates Fertility through Controlling Cell Proliferation in the Germline and Nutrient Synthesis in the Intestine

Huang

Zhao

et al. 2013

PLoS ONE

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RBBP6 (retinoblastoma binding protein 6, also known as PACT or P2P-R in humans) is a multi-domain protein that functions in multiple processes, such as mitosis, cell differentiation, and cell apoptosis. RBBP6 is evolutionarily conserved and is present in unicellular organisms to mammals. Studies of RBBP6 have mostly focused on its RB- and p53-binding domains, which are found exclusively in mammals. Here, we investigated the C. elegans homolog of RBBP6 to explore the functional roles of its other domains. We found that RBPL-1, the homolog of RBBP6 in C. elegans, is indispensable for worm development. RNAi silencing of rbpl-1 led to embryonic lethality, as well as defects in oocyte production and intestine development. rbpl-1 RNAi worms showed defects in germ cell proliferation, suggesting that RBPL-1 regulates mitosis. Moreover, RNAi silencing of rbpl-1 inhibited nutrient synthesis in the worm intestine. RBPL-1, as a nucleolus protein, was found to be expressed in diverse tissues and necessary for both germline and soma development. Using microarray analysis, we identified ≈700 genes whose expression levels were changed at least 10-fold in rbpl-1 worms. We propose that RBPL-1, like its yeast homolog, may regulate gene expression as an mRNA cleavage and polyadenylation factor. Taken together, the findings from this study reveal that RBPL-1 plays a pivotal role in C. elegans germline and soma development, suggesting that the functions of RBBP6 are conserved in diverse eukaryotic species.

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Solution Structure of RING Finger-like Domain of Retinoblastoma-binding Protein-6 (RBBP6) Suggests It Functions as a U-box

Cited by 16 publications

References 60 publications

Human BRCA1–BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection

Human BRCA1–BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection

Efficient mRNA Polyadenylation Requires a Ubiquitin-Like Domain, a Zinc Knuckle, and a RING Finger Domain, All Contained in the Mpe1 Protein

The C. elegans Homolog of RBBP6 (RBPL-1) Regulates Fertility through Controlling Cell Proliferation in the Germline and Nutrient Synthesis in the Intestine

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