Breast cancer progression, treatment resistance, and relapse are thought to originate from a small population of tumor cells, breast cancer stem cells (BCSCs). Identification of factors critical for BCSC function is therefore vital for the development of therapies. Here, we identify the arginine methyltransferase PRMT5 as a key in vitro and in vivo regulator of BCSC proliferation and self-renewal and establish FOXP1, a winged helix/forkhead transcription factor, as a critical effector of PRMT5-induced BCSC function. Mechanistically, PRMT5 recruitment to the FOXP1 promoter facilitates H3R2me2s, SET1 recruitment, H3K4me3, and gene expression. Our findings are clinically significant, as PRMT5 depletion within established tumor xenografts or treatment of patient-derived BCSCs with a pre-clinical PRMT5 inhibitor substantially reduces BCSC numbers. Together, our findings highlight the importance of PRMT5 in BCSC maintenance and suggest that small-molecule inhibitors of PRMT5 or downstream targets could be an effective strategy eliminating this cancer-causing population.

Protein post-translation modification plays an important role in regulating DNA repair; however, the role of arginine methylation in this process is poorly understood. Here we identify the arginine methyltransferase PRMT5 as a key regulator of homologous recombination (HR)-mediated double-strand break (DSB) repair, which is mediated through its ability to methylate RUVBL1, a cofactor of the TIP60 complex. We show that PRMT5 targets RUVBL1 for methylation at position R205, which facilitates TIP60-dependent mobilization of 53BP1 from DNA breaks, promoting HR. Mechanistically, we demonstrate that PRMT5-directed methylation of RUVBL1 is critically required for the acetyltransferase activity of TIP60, promoting histone H4K16 acetylation, which facilities 53BP1 displacement from DSBs. Interestingly, RUVBL1 methylation did not affect the ability of TIP60 to facilitate ATM activation. Taken together, our findings reveal the importance of PRMT5-mediated arginine methylation during DSB repair pathway choice through its ability to regulate acetylation-dependent control of 53BP1 localization.

Priapism defined as persistent, painful and prolonged penile erection, was previously thought to be associated only with the use of the older, conventional first generation or typical antipsychotic medications as well as some other medications, notably, trazodone. The mechanism of priapism associated with antipsychotics is not clear but is thought to be related to α-adrenergic blockage that is mediated by the α receptors in the corpora cavernosa of the penis. Atypical antipsychotics, also known as second-generation antipsychotics, owing to their favorable side effect profile, are being prescribed with increasing frequency and are not as frequently considered to cause priapism. Some case reports reporting this side effect with their use, however, are found. Pubmed and Ovid databases were searched to obtain all articles and case reports of antipsychotic drug-induced priapism. Key search words included ‘priapism’, ‘antipsychotics’ and ‘drug-induced priapism’. References of all identified studies were also reviewed. A total of 50 publications were obtained. Most of the atypical antipsychotics have been reported to cause priapism. These cases have occurred in patients shortly after having been started on the antipsychotic medications as well as in those who have been on them for an extended period of time without modification in dosage, and have also occurred sometimes, with the addition of another antipsychotic, lithium or serotonin-specific reuptake inhibitor. Priapism has been documented with nearly all the atypical antipsychotic medications. It is, however, a rarely reported side effect and therefore, underappreciated. Priapism can cause irreversible erectile dysfunction and is a urologic emergency. Clinicians should monitor patients on these medications for this rare, yet significant side effect. Furthermore, caution must be used when adding new drugs to the regimen and patients should be closely monitored for this side effect. Educating patients about the risk of developing priapism would help increase awareness of the side effect and promote early reporting thereby, decreasing long-term morbidity.

Background: The spread of COVID-19 has affected people’s daily lives, and the lockdown may have led to a disruption of daily activities and a decrease of people’s mental health. Aim: To identify correlates of adults’ mental health during the COVID-19 lockdown in Belgium and to assess the role of meaningful activities in particular. Methods: A cross-sectional web survey for assessing mental health (General Health Questionnaire), resilience (Connor-Davidson Resilience Scale), meaning in activities (Engagement in Meaningful Activities Survey), and demographics was conducted during the first Belgian lockdown between April 24 and May 4, 2020. The lockdown consisted of closing schools, non-essential shops, and recreational settings, employees worked from home or were technically unemployed, and it was forbidden to undertake social activities. Every adult who had access to the internet and lived in Belgium could participate in the survey; respondents were recruited online through social media and e-mails. Hierarchical linear regression was used to identify key correlates. Results: Participants (N = 1781) reported low mental health (M = 14.85/36). In total, 42.4% of the variance in mental health could be explained by variables such as gender, having children, living space, marital status, health condition, and resilience (β = −.33). Loss of meaningful activities was strongly related to mental health (β = −.36) and explained 9% incremental variance (R² change = .092, p < .001) above control variables. Conclusions: The extent of performing meaningful activities during the COVID-19 lockdown in Belgium was positively related to adults’ mental health. Insights from this study can be taken into account during future lockdown measures in case of pandemics.