ARMC5 is part of an RPB1-specific ubiquitin ligase implicated in adrenal hyperplasia

Lao, Linjiang; Bourdeau, Isabelle; Gagliardi, Lucia; He, Xiao; Shi, Wei; Hao, Bingbing; Tan, Minjia; Hu, Yan; Peng, Junzheng; Coulombe, Benoit; Torpy, David J.; Scott, Hamish S.; Lacroix, André; Luo, Hongyu; Wu, Jiangping

doi:10.1093/nar/gkac483

Cited by 17 publications

(20 citation statements)

References 92 publications

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“…We previously reported that ARMC5 was expressed predominantly in the cytosol [ 19 ]. However, we later found that if nuclear export was blocked, ARMC5 appeared in the nuclei of transfected HEK293 cells [ 45 ]. To determine the location of ARMC5 expression in neuronal cells, we transfected SK-N-SH neuronal cells with ARMC5-expressing constructs.…”

Section: Resultsmentioning

confidence: 99%

ARMC5 controls the degradation of most Pol II subunits, and ARMC5 mutation increases neural tube defect risks in mice and humans

Luo,

Lao,

et al. 2024

Genome Biol

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Background Neural tube defects (NTDs) are caused by genetic and environmental factors. ARMC5 is part of a novel ubiquitin ligase specific for POLR2A, the largest subunit of RNA polymerase II (Pol II). Results We find that ARMC5 knockout mice have increased incidence of NTDs, such as spina bifida and exencephaly. Surprisingly, the absence of ARMC5 causes the accumulation of not only POLR2A but also most of the other 11 Pol II subunits, indicating that the degradation of the whole Pol II complex is compromised. The enlarged Pol II pool does not lead to generalized Pol II stalling or a generalized decrease in mRNA transcription. In neural progenitor cells, ARMC5 knockout only dysregulates 106 genes, some of which are known to be involved in neural tube development. FOLH1, critical in folate uptake and hence neural tube development, is downregulated in the knockout intestine. We also identify nine deleterious mutations in the ARMC5 gene in 511 patients with myelomeningocele, a severe form of spina bifida. These mutations impair the interaction between ARMC5 and Pol II and reduce Pol II ubiquitination. Conclusions Mutations in ARMC5 increase the risk of NTDs in mice and humans. ARMC5 is part of an E3 controlling the degradation of all 12 subunits of Pol II under physiological conditions. The Pol II pool size might have effects on NTD pathogenesis, and some of the effects might be via the downregulation of FOLH1. Additional mechanistic work is needed to establish the causal effect of the findings on NTD pathogenesis.

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Section: Resultsmentioning

confidence: 99%

ARMC5 controls the degradation of most Pol II subunits, and ARMC5 mutation increases neural tube defect risks in mice and humans

Luo,

Lao,

et al. 2024

Genome Biol

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“…In line with this, it has been proposed that NEDD4 first mono-ubiquitylates RPB1 and then Elongin ABC -Cullin5 poly-ubiquitylates it, targeting RPB1 for proteasomal degradation [ 40 , 41 , 42 ]. Moreover, BRCA1/BARD1 and Cull3-based ARMC5 were also proposed to act as RPB1 E3 ligases [ 43 , 44 ], suggesting that several steps of ubiquitylation/de-ubiquitylation may be necessary for a timely-controlled RPB1 eviction from chromatin and degradation [ 26 ]. The fact that many E3 ligases have been implicated in RPB1 ubiquitylation might be either an indicator of a multistep process controlling RPB1 ubiquitylation and/or multiple mechanisms controlling RNAPII fate, with different E3 ligase complexes involved in different scenarios.…”

Section: Rnapii Ubiquitylationmentioning

confidence: 99%

DNA Damage-Induced RNAPII Degradation and Its Consequences in Gene Expression

Muñoz

Beckerman

Choudhary

et al. 2022

Genes

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RPB1, the major and catalytic subunit of human RNA Polymerase II (RNAPII), is specifically degraded by the ubiquitin–proteasome system upon induction of DNA damage by different agents, such as ultraviolet (UV) light. The “last resort” model of RNAPII degradation states that a persistently stalled RNAPII is degraded at the site of the DNA lesion in order to facilitate access to Nucleotide Excision Repair (NER) factors, thereby promoting repair in template strands of active genes. Recent identification and mutation of the lysine residue involved in RPB1 ubiquitylation and degradation unveiled the relevance of RNAPII levels in the control of gene expression. Inhibition of RNAPII degradation after UV light exposure enhanced RNAPII loading onto chromatin, demonstrating that the mere concentration of RNAPII shapes the gene expression response. In this review, we discuss the role of RNAPII ubiquitylation in NER-dependent repair, recent advances in RPB1 degradation mechanisms and its consequences in gene expression under stress, both in normal and repair deficient cells.

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“…Intracellular protein homeostasis is regulated by protein synthesis and degradation 1 . Proteins are degraded by two main proteolytic systems: the autophagy‐lysosome pathway and the ubiquitin‐proteasome system 2 .…”

Section: Introductionmentioning

confidence: 99%

“…Intracellular protein homeostasis is regulated by protein synthesis and degradation. 1 Proteins are degraded by two main proteolytic systems: the autophagy‐lysosome pathway and the ubiquitin‐proteasome system. 2 Ubiquitination mediates the targeting of a substrate to the proteasome and the lysosome, a significant site for protein degradation.…”

Section: Introductionmentioning

confidence: 99%

BRCC36 associates with FLT3‐ITD to regulate its protein stability and intracellular signaling in acute myeloid leukemia

Liu,

Isaji,

Komatsu

et al. 2024

Cancer Science

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Fms‐like tyrosine kinase‐3 (FLT3) is a commonly mutated gene in acute myeloid leukemia (AML). The two most common mutations are the internal‐tandem duplication domain (ITD) mutation and the tyrosine kinase domain (TKD) mutation. FLT3‐ITD and FLT3‐TKD exhibit distinct protein stability, cellular localization, and intracellular signaling. To understand the underlying mechanisms, we performed proximity labeling with TurboID to identify proteins that regulate FLT3‐ITD or ‐TKD differently. We found that BRCA1/BRCA2‐containing complex subunit 36 (BRCC36), a specific K63‐linked polyubiquitin deubiquitinase, was exclusively associated with ITD, not the wild type of FLT3 and TKD. Knockdown of BRCC36 resulted in decreased signal transducers and activators of transcription 5 phosphorylation and cell proliferation in ITD cells. Consistently, treatment with thiolutin, an inhibitor of BRCC36, specifically suppressed cell proliferation and induced cell apoptosis in ITD cells. Thiolutin efficiently affected leukemia cell lines expressing FLT3‐ITD cell viability and exhibited mutual synergies with quizartinib, a standard clinical medicine for AML. Furthermore, mutation of the lysine at 609 of ITD led to significant suppression of K63 polyubiquitination and decreased its stability, suggesting that K609 is a critical site for K63 ubiquitination specifically recognized by BRCC36. These data indicate that BRCC36 is a specific regulator for FLT3‐ITD, which may shed light on developing a novel therapeutic approach for AML.

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ARMC5 is part of an RPB1-specific ubiquitin ligase implicated in adrenal hyperplasia

Cited by 17 publications

References 92 publications

ARMC5 controls the degradation of most Pol II subunits, and ARMC5 mutation increases neural tube defect risks in mice and humans

ARMC5 controls the degradation of most Pol II subunits, and ARMC5 mutation increases neural tube defect risks in mice and humans

DNA Damage-Induced RNAPII Degradation and Its Consequences in Gene Expression

BRCC36 associates with FLT3‐ITD to regulate its protein stability and intracellular signaling in acute myeloid leukemia

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