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Fondazione Italiana per la Ricerca sul Cancro FIRC 18112 Sina Atashpaz.Fondazione Umberto Veronesi Sina Atashpaz Associazione Italiana per la Ricerca sul Cancro AIRC 5xmille METAMECH program Vincenzo Costanzo Giovanni Armenise-Harvard Foundation Vincenzo Costanzo European Research Council Consolidator grant 614541 Vincenzo Costanzo Associazione Italiana per la Ricerca sul Cancro Fellowship 23961 Negar ArghavanifarDanish Cancer Society KBVU-2014 Andres Joaquin Lopez-Contreras Danish Council for Independent Research Sapere Aude, DFF Starting Grant 2014 Andres Joaquin Lopez-Contreras European Research Council ERC-2015-STG-679068 Andres Joaquin Lopez-Contreras Danish National Research Foundation DNRF115 Andres Joaquin Lopez-Contreras The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Unrepaired DNA damage during embryonic development can be potentially inherited by a large population of cells. However, the quality control mechanisms that minimize the contribution of damaged cells to developing embryos remain poorly understood. Here, we uncovered an ATR- and CHK1-mediated transcriptional response to replication stress (RS) in mouse embryonic stem cells (ESCs) that induces genes expressed in totipotent two-cell (2C) stage embryos and 2C-like cells. This response is mediated by Dux, a multicopy retrogene defining the cleavage-specific transcriptional program in placental mammals. In response to RS, DUX triggers the transcription of 2C-like markers such as murine endogenous retrovirus-like elements (MERVL) and Zscan4. This response can also be elicited by ETAA1-mediated ATR activation in the absence of RS. ATR-mediated activation of DUX requires GRSF1-dependent post-transcriptional regulation of Dux mRNA. Strikingly, activation of ATR expands ESCs fate potential by extending their contribution to both embryonic and extra-embryonic tissues. These findings define a novel ATR dependent pathway involved in maintaining genome stability in developing embryos by controlling ESCs fate in response to RS. Sí

Although numerous long noncoding RNAs (lncRNAs) have been identified, our understanding of their roles in mammalian physiology remains limited. Here, we investigated the physiologic function of the conserved lncRNA Norad in vivo. Deletion of Norad in mice results in genomic instability and mitochondrial dysfunction, leading to a dramatic multi-system degenerative phenotype resembling premature aging. Loss of tissue homeostasis in Norad-deficient animals is attributable to augmented activity of PUMILIO proteins, which act as post-transcriptional repressors of target mRNAs to which they bind. Norad is the preferred RNA target of PUMILIO2 (PUM2) in mouse tissues and, upon loss of Norad, PUM2 hyperactively represses key genes required for mitosis and mitochondrial function. Accordingly, enforced Pum2 expression fully phenocopies Norad deletion, resulting in rapid-onset aging-associated phenotypes. These findings provide new insights and open new lines of investigation into the roles of noncoding RNAs and RNA binding proteins in normal physiology and aging., eLife digest Only a tiny portion of our genetic material contains the information required to create proteins, the workhorses of the body. The rest of our DNA, however, is not useless: some of it can be transcribed to create molecules known as non-coding RNAs, which are increasingly scrutinized by scientists. For example, a non-coding RNA called NORAD acts as a guardian of the genome by reducing the activity of a protein named PUMILIO. Without NORAD, PUMILIO becomes overactive, and this causes problems as genetic information is split between two ‘daughter cells’ when a cell divides. Defects in the amount of genetic material in cells have been linked with faster aging in animals. In addition, some studies suggest that as animals get older, the levels of NORAD in the body decrease, while the levels of PUMILIO increase. However, the precise role that NORAD may play in aging remains unclear. To address this question, Kopp et al. engineered mutant mice that lack Norad (the mouse equivalent of human NORAD) and carefully monitored how they grew and developed. The animals looked normal at birth, but they seemed to age faster: for instance, their fur became thin and gray, and their brains developed age-related abnormalities much sooner than normal mice. At the level of individual cells, losing Norad was also associated with problems often seen in old age. The mutant animals were more likely to have incorrect amounts of genetic information in their cells, and they had defects in the cell compartments that create the energy necessary for life. Further experiments showed that these issues were driven by PUMILIO being hyperactive. Overall, the work by Kopp et al. reveal that the non-coding RNA Norad is essential to keep PUMILIO activity in check and to prevent problems associated with aging from appearing in young animals. Further studies are now needed to take a closer look at how NORAD and other non-coding RNAs keep us healthy.

Although numerous long noncoding RNAs (lncRNAs) have been identified, our understanding of their roles in mammalian physiology remains limited. Here, we investigated the physiologic function of the conserved lncRNA