Talks by Loic BROIX and Patricia UGUEN

Loic BROIX
Sorbonne Université - NeuroSU Site du Fer à Moulin - CNRS UMR8265/Inserm U1341

Title:
Regulation of local translation and axon development by m6A RNA methylation

Abstract:
The localization and translation of mRNAs in neurons are regulated by RNA-binding proteins and play a crucial role in neuronal development. In this study, we provide evidence that the multifunctional RNA-binding protein Adenomatous Polyposis Coli (APC) is encoded by an mRNA modified with N6-methyladenosine (m6A). This modification enhances APC translation in neuronal somata through YTHDF m6A reader proteins. Disruptions in APC expression, caused by reduced levels of the m6A writer METTL14 or the reader YTHDF1, or by overexpression of METTL14 mutants carrying autismand schizophrenia-associated human missense mutations, impair the transport and local translation of APC-regulated target mRNA β-actin in axons and growth cones. Consequently, these disruptions hinder axon development both in vitro and in vivo. Our findings reveal a mechanism by which m6Adependent global expression of the RNA-binding protein APC regulates axonal mRNA translation and development.

Patricia UGUEN
CNRS UMR3348 Genome integrity, RNA and Cancer, Institut Curie, University Paris-Saclay

Title: Does 53BP1 bind to RNA-DNA primers to prevent the activation of innate immune response?

Abstract:
Genomic instability has many incomes, either endogenous or exogenous sources. In addition to pathogenic DNA, self-DNA, which are accumulated in cytosol can activate innate immune responses, leading to the production of type 1 interferon (IFN) stimulated genes (ISG). This activation would be mediated by the cGAS-STING pathway. 53BP1 is well known as a mediator of the double-strand break repair, but it is also involved into fork protection under replicative stress. The team has recently found that 53BP1 protein binds to RNA-DNA primers in unperturbated DNA replication. We ask whether the binding activity of 53BP1 can play a protective role against uncontrolled release of RNA- DNA chimeras. We have shown that depletion of 53BP1 activates expression of many markers of inflammatory type I interferons.