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Endocrine Abstracts (2023) 90 RC5.4 | DOI: 10.1530/endoabs.90.RC5.4

ECE2023 Rapid Communications Rapid Communications 5: Adrenal and Cardiovascular Endocrinology 1 (6 abstracts)

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is likely a genome instability disease due to ARMC5’s role in resolving transcription-replication conflict

Linjiang Lao 1 , Isabelle Bourdeau 1 , Lucia Gagliardi 2 , Xiao He 1 , David Torpy 2 , Hamish Scott 3 , Andre Lacroix 1 , Hongyu Luo 1 & Jiangping Wu 1

1Centre Hospitalier de l’Universite de Montreal (CHUM), CHUM Research Center, Montréal, Canada; 2Royal Adelaide Hospital, Royal Adelaide Hospital, Adelaide, Australia; 3Adelaide Medical School, Adelaide, Australia

ARMC5 mutations are associated with PBMAH risks, but the ARMC5 action mechanism remains unknown. We discovered that ARMC5 was part of a novel ubiquitin ligase (E3) specific for RPB1, the largest Pol II subunit. ARMC5 deletion significantly reduced RPB1 ubiquitination and increased RPB1 accumulation. Surprisingly, the degradation of not only RPB1 but all the 12 subunits of Pol II was compromised in the absence of ARMC5, suggesting that this E3 acts on RPB1 and molecules in its vicinity, and ARMC5 mutation causes an enlarged Pol II pool. The stalled Pol II due to DNA damage needs to be removed by degradation via the ubiquitin/proteasome system, or else the transcription machinery will suffer from a genome-wide jam and transcription decrease. However, a combined analysis of RPB1 ChIP-seq and RNA-seq of the ARMC5 KO adrenals revealed that a lack of this major Pol II-specific E3 did not lead to a generalized transcription decrease. This suggests that either under physiological conditions, Pol II stalling is not common, or there is a so-far unknown mechanism to recycle the stalled Pol II. Although ARMC5 mutations are associated with adrenal hyperplasia, the proliferation of most types of KO cells was reduced. This raises an intriguing possibility that the physiological function of the E3 is to remove Pol II from the DNA track to resolve the transcription-replication conflict. Failure to do so in the S phase will slow down replication accompanied by genome instability, which is a pro-oncogenic condition. The enlarged Pol II pool in the KO adrenals led to differential expression of 1486 genes. The majority of these genes were upregulated, and some of the upregulated ones were oncogenes. The expression of StAR, the rate-limiting enzyme in cortisol biogenesis, was reduced, probably as a secondary effect of the enlarged Pol II pool; this decrease explains the reduced cortisol secretion per cell in PBMAH. ARMC5 was previously incorrectly called a tumor suppressor gene. We now know that it affects more upstream processes controlling the general replication and transcription. Based on our findings, we propose the following model. The defective ARMC5-containing E3 leads to an enlarged Pol II pool and compromises transcription-replication conflict resolution. The former upregulates some oncogenes. The latter causes oncogenic genome instability and, at the same time, reduced replication. The sum effect of all these conflicting forces is the pathogenesis of slow-growing tumors or hyperplasia such as PBMAH.

Volume 90

25th European Congress of Endocrinology

Istanbul, Turkey
13 May 2023 - 16 May 2023

European Society of Endocrinology 

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