Nuclear Lipid Droplet Birth during Replicative Stress

The nuclear membrane defines the boundaries that confine, protect and shape the genome. As such, its blebbing, ruptures and deformations are known to compromise the integrity of genetic material. Yet, drastic transitions of the nuclear membrane such as its invagination towards the nucleoplasm or its capacity to emit nuclear lipid droplets (nLD) have not been evaluated with respect to their impact on genome dynamics. To begin assessing this, in this work we used Saccharomyces cerevisiae as a model to ask whether a selection of genotoxins can trigger the formation of nLD. We report that nLD formation is not a general feature of all genotoxins, but of those engendering replication stress. Exacerbation of endogenous replication stress by genetic tools also elicited nLD formation. When exploring the lipid features of the nuclear membrane at the base of this emission, we revealed a link with the unsaturation profile of its phospholipids and, for the first time, of its sterol content. We propose that stressed replication forks may stimulate nLD birth by anchoring to the inner nuclear membrane, provided that the lipid context is adequate. Further, we point to a transcriptional feed-back process that counteracts the membrane's proneness to emit nLD. With nLD representing platforms onto which genome-modifying reactions can occur, our findings highlight them as important players in the response to replication stress.

Automated summary

The nuclear membrane plays an important role in confining and protecting the genome, and disruptions in its structure can compromise genetic material. This study investigates the formation of nuclear lipid droplets (nLD) and their potential impact on genome dynamics. The results suggest that genotoxins that cause replication stress can trigger nLD formation, and the lipid context of the nuclear membrane is crucial in this process. Furthermore, a transcriptional feedback process is identified that counteracts the membrane's tendency to emit nLD. These findings highlight the importance of nLD in the response to replication stress.