U. (2021).Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition. Nature, 590(7846).

Protein arginine methyltransferases (PRMTs) catalyze arginine methylation on both chromatin-bound and cytoplasmic proteins. Accumulating evidence supports the involvement of PRMT5, the major type II PRMT, in cell survival and differentiation pathways that are important during development and in tumorigenesis. PRMT5 is an attractive drug target in various cancers, and inhibitors are currently in oncological clinical trials. Nonetheless, given the complex biology of PRMT5 and its multiple nonhistone substrates, it is paramount to fully characterize these dynamic changes in methylation and to link them to the observed anticancer effects to fully understand the functions of PRMT5 and the consequences of its inhibition. Here, we used a newly established pipeline coupling stable isotope labeling with amino acids in cell culture (SILAC) with immunoenriched methyl peptides to globally profile arginine monomethylation and symmetric dimethylation after PRMT5 inhibition by a selective inhibitor. We adopted heavy methyl SILAC as an orthogonal validation method to reduce the false discovery rate. Through in vitro methylation assays, we validated a set of PRMT5 targets identified by mass spectrometry and provided previously unknown mechanistic insights into the preference of the enzyme to methylate arginine sandwiched between two neighboring glycines (a Gly-Arg-Gly, or “GRG,” sequence). Our analysis led to the identification of previously unknown PRMT5 substrates, thus both providing insight into the global effects of PRMT5 and its inhibition in live cells, beyond chromatin, and refining our knowledge of its substrate specificity.

This article is based on a grounded theory analysis of interviews with transgender-identified people from different regions of the United States. Participants held a variety of gender identities under the transgender rubric (e.g., crossdresser, transman, transwoman, butch lesbian). Interviews explored the participants' experiences in arriving at their gender identity. This article presents three clusters of findings related to the common processes of transgender identity development. This process was made possible by accessibility of transgender narratives that injected hope into what was a childhood replete with criticism and scrutiny. Ultimately, participants came to their identities through balancing a desire for authenticity with demands of necessity--meaning that they weighed their internal gender experience with considerations about their available resources, coping skills, and the consequences of gender transitions. The implications of these findings are considered in terms of their contribution to gender theory, research, and clinical support for transgender clients.

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