Nono induces Gadd45b to mediate DNA repair.

RNA-binding proteins are frequently deregulated in cancer and emerge as effectors of the DNA damage response (DDR). The non-POU domain-containing octamer-binding protein NONO/p54nrb is a multifunctional RNA-binding protein that not only modulates the production and processing of mRNA, but also promotes the repair of DNA double-strand breaks (DSBs). Here, we investigate the impact of Nono deletion in the murine KP (KRas G12D , Trp53 -/- ) cell-based lung cancer model. We show that the deletion of Nono impairs the response to DNA damage induced by the topoisomerase II inhibitor etoposide or the radiomimetic drug bleomycin. Nono-deficient KP (KPN) cells display hyperactivation of DSB signalling and high levels of DSBs. The defects in the DDR are accompanied by reduced RNA polymerase II promoter occupancy, impaired nascent RNA synthesis, and attenuated induction of the DDR factor growth arrest and DNA damage-inducible beta (Gadd45b). Our data characterise Gadd45b as a putative Nono-dependent effector of the DDR and suggest that Nono mediates a genome-protective crosstalk of the DDR with the RNA metabolism via induction of Gadd45b.

Tyrosine 1-phosphorylated RNA polymerase II transcribes PROMPTs to facilitate proximal promoter pausing and induce global transcriptional repression in response to DNA damage.

DNA damage triggers a complex transcriptional response that involves both activation and repression of gene expression. In this study, we investigated global changes in transcription in response to ionizing irradiation (IR), which induces double-strand breaks in DNA. We used mNET-seq to profile nascent transcripts bound to different phosphorylated forms of the RNA polymerase II (RNA Pol II) C-terminal domain (CTD). We found that IR leads to global transcriptional repression of protein-coding genes, accompanied by an increase in antisense transcripts near promoters, called PROMPTs, transcribed by RNA Pol II phosphorylated on tyrosine 1 (Y1P) residue of the CTD. These Y1P-transcribed PROMPTs are enriched for PRC2 binding sites and associated with RNA Pol II proximal promoter pausing. We show the interaction between Y1P RNA Pol II and PRC2, as well as PRC2 binding to PROMPTs. Inhibition of PROMPTs or depletion of PRC2 leads to loss of transcriptional repression. Our results reveal a novel function of Y1P-dependent PROMPTs in mediating PRC2 recruitment to chromatin and RNA Pol II promoter pausing in response to DNA damage.

Mental health, gender, and higher education attainment.

We compared the mental health of higher education students with that of nonstudents. Moreover, we examined whether the mental health of students predicts their probability of obtaining a higher education degree, and whether the extent to which mental health affects educational attainment varies by gender. Drawing on a risk and resilience framework, we considered five facets of mental health that may be implicated in distinct ways in the educational attainment process: positive attitude towards life, self-esteem, self-efficacy, negative affectivity, and perceived stress. We used data from a nationally representative panel study from Switzerland (Nstudents = 2070, 42.8% male; Nnonstudents = 3755, 45.9% male). The findings suggest that overall, the mental health of higher education students was relatively similar to that of nonstudents, although students exhibited slightly higher self-esteem, slightly weaker self-efficacy, greater negative affectivity, and higher levels of perceived stress. The effects of different facets of mental health on higher education degree attainment were mostly statistically and/or practically insignificant. However, positive attitudes towards life had a substantial positive effect on the probability of being awarded a higher education degree. Mental health was equally important for male and female students' educational attainment. Supplementary Information: The online version of this article (10.1007/s11618-023-01187-3) contains supplementary material, which is available to authorized users.

Nucleolar detention of NONO shields DNA double-strand breaks from aberrant transcripts.

RNA-binding proteins emerge as effectors of the DNA damage response (DDR). The multifunctional non-POU domain-containing octamer-binding protein NONO/p54nrb marks nuclear paraspeckles in unperturbed cells, but also undergoes re-localization to the nucleolus upon induction of DNA double-strand breaks (DSBs). However, NONO nucleolar re-localization is poorly understood. Here we show that the topoisomerase II inhibitor etoposide stimulates the production of RNA polymerase II-dependent, DNA damage-inducible antisense intergenic non-coding RNA (asincRNA) in human cancer cells. Such transcripts originate from distinct nucleolar intergenic spacer regions and form DNA-RNA hybrids to tether NONO to the nucleolus in an RNA recognition motif 1 domain-dependent manner. NONO occupancy at protein-coding gene promoters is reduced by etoposide, which attenuates pre-mRNA synthesis, enhances NONO binding to pre-mRNA transcripts and is accompanied by nucleolar detention of a subset of such transcripts. The depletion or mutation of NONO interferes with detention and prolongs DSB signalling. Together, we describe a nucleolar DDR pathway that shields NONO and aberrant transcripts from DSBs to promote DNA repair.

Mental health and educational attainment: How developmental stage matters.

Developmental science suggests that the consequences of mental health problems for life-course outcomes may depend on the timing of their onset. This study investigated the extent to which mental health predicted educational attainment at ages 17, 20, and 25 and whether gender moderated the links between mental health and educational attainment. It used data from Next Steps, a nationally representative panel survey of individuals born in 1989/1990 in England (N = 15,594, 48% female, 33% ethnic minority). The findings suggest that differences in mental health were more consequential for educational attainment during adolescence than in young adulthood. On average, girls attained higher levels of education than boys, but gender did not moderate the role that mental health played for educational attainment. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Revisiting the power of future expectations and educational path dependencies.

Individuals from more advantaged socioeconomic backgrounds and those with loftier future expectations typically have higher educational attainment. However, it is important to understand just how consequential future expectations are for educational attainment independent of socioeconomic origins-because these expectations might enable intergenerational social mobility. Moreover, it is unclear whether institutional structures moderate the influences of socioeconomic origins and future expectations on educational attainment. I address these questions by analyzing educational attainment as it relates to transitions in a system that offers multiple educational tracks. Using data from a 15-year longitudinal study conducted in Switzerland (N = 4986), I analyze transitions from lower- to upper-secondary education (academic vs. vocational tracks) and from there to university. Path models reveal that both socioeconomic origins and future expectations are significantly associated with individuals' probability of moving along academic paths and into university, but future expectations have a strong unique predictive power even when controlling for socioeconomic origins. However, because the education system partially channels educational trajectories along distinct educational tracks, it minimizes the beneficial effect of future expectations on educational attainment and-by extension-intergenerational social mobility. I conclude that socioeconomic advantage and optimistic future expectations may only shape educational attainment to the extent that institutional opportunity structures allow such resources to take effect.

Making it to the Academic Path in a Tracked Education System: The Interplay of Individual Agency and Social Origin in Early Educational Transitions.

Little is known about the role of agency in transitions in tracked education systems or whether it varies by socioeconomic background. This study addressed this gap by estimating structural equation models based on longitudinal data that are representative of the German- and French-speaking parts of Switzerland (N = 1273 individuals, surveyed from age 6 to 18, mean age at wave 1: Mage = 6.54, SDage = 0.50, female = 49%). The findings reveal that agency (captured by study effort and occupational aspirations) and socioeconomic background (measured by parental education and family income) significantly predicted students' transitions to academically demanding tracks in lower- and upper-secondary education. In the transition to upper-secondary education, students with fewer socioeconomic resources benefitted less than their more advantaged peers from ambitious aspirations, but they benefitted more from exerting effort. These findings suggest that both an optimistic forward-looking orientation and the exertion of effort are required to make it to an academic track. Effort may serve as a "substitutive" resource for less socioeconomically advantaged students, whereas ambitious aspirations may enhance the positive effect of family socioeconomic resources on academic educational trajectories. Overall, the evidence from this study calls for greater attention to investigating not only how agency shapes adolescents' educational trajectories and opportunities but also how its role differs across social groups.

Disentangling the interplay of the sense of belonging and institutional channels in individuals' educational trajectories.

Accumulating evidence indicates that students' sense of school belonging has a substantial positive effect on educational attainment. At the same time, life course and life span developmental theories suggest that the benefits of a sense of school belonging could be weakened by the channeling effects of education systems that assign students to distinct educational tracks that lead otherwise similar students to quite different educational destinations. The current study analyzed the extent to which the sense of school belonging predicted educational trajectories in a system that partially channels students into distinct tracks. It assessed educational trajectories as they relate to transitions at two critical junctures of the system-the transition from lower- to upper-secondary education, and from upper-secondary to tertiary (university) education. The study used data from a nationally representative panel survey that followed participants from age 15 to 30 (N = 4,986, 44% male, 12.9% immigrants). Findings indicated that students with a stronger sense of school belonging were more likely to continue in or transition into academic tracks. However, the benefits of students' sense of belonging were bounded by the system's channeling structure. While for students in academic tracks, the sense of school belonging strongly predicted the probability of continuing in academic tracks, it only marginally predicted the probability of moving into academic tracks for those whose educational career began in more vocationally oriented tracks. Hence the sense of school belonging may influence academic trajectories only inasmuch as institutional structures allow it to, because these structures differentially enable and constrain such trajectories. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Observing many researchers using the same data and hypothesis reveals a hidden universe of uncertainty.

This study explores how researchers' analytical choices affect the reliability of scientific findings. Most discussions of reliability problems in science focus on systematic biases. We broaden the lens to emphasize the idiosyncrasy of conscious and unconscious decisions that researchers make during data analysis. We coordinated 161 researchers in 73 research teams and observed their research decisions as they used the same data to independently test the same prominent social science hypothesis: that greater immigration reduces support for social policies among the public. In this typical case of social science research, research teams reported both widely diverging numerical findings and substantive conclusions despite identical start conditions. Researchers' expertise, prior beliefs, and expectations barely predict the wide variation in research outcomes. More than 95% of the total variance in numerical results remains unexplained even after qualitative coding of all identifiable decisions in each team's workflow. This reveals a universe of uncertainty that remains hidden when considering a single study in isolation. The idiosyncratic nature of how researchers' results and conclusions varied is a previously underappreciated explanation for why many scientific hypotheses remain contested. These results call for greater epistemic humility and clarity in reporting scientific findings.

In vivo Proximity Labeling of Nuclear and Nucleolar Proteins by a Stably Expressed, DNA Damage-Responsive NONO-APEX2 Fusion Protein.

Cellular stress can induce DNA lesions that threaten the stability of genes. The DNA damage response (DDR) recognises and repairs broken DNA to maintain genome stability. Intriguingly, components of nuclear paraspeckles like the non-POU domain containing octamer-binding protein (NONO) participate in the repair of DNA double-strand breaks (DSBs). NONO is a multifunctional RNA-binding protein (RBP) that facilitates the retention and editing of messenger (m)RNA as well as pre-mRNA processing. However, the role of NONO in the DDR is poorly understood. Here, we establish a novel human U2OS cell line that expresses NONO fused to the engineered ascorbate peroxidase 2 (U2OS:NONO-APEX2-HA). We show that NONO-APEX2-HA accumulates in the nucleolus in response to DNA damage. Combining viability assays, subcellular localisation studies, coimmunoprecipitation experiments and in vivo proximity labeling, we demonstrate that NONO-APEX2-HA is a stably expressed fusion protein that mimics endogenous NONO in terms of expression, localisation and bona fide interactors. We propose that in vivo proximity labeling in U2OS:NONO-APEX2-HA cells is capable for the assessment of NONO interactomes by downstream assays. U2OS:NONO-APEX2-HA cells will likely be a valuable resource for the investigation of NONO interactome dynamics in response to DNA damage and other stimuli.

Compartment-Specific Proximity Ligation Expands the Toolbox to Assess the Interactome of the Long Non-Coding RNA NEAT1.

The nuclear paraspeckle assembly transcript 1 (NEAT1) locus encodes two long non-coding (lnc)RNA isoforms that are upregulated in many tumours and dynamically expressed in response to stress. NEAT1 transcripts form ribonucleoprotein complexes with numerous RNA-binding proteins (RBPs) to assemble paraspeckles and modulate the localisation and activity of gene regulatory enzymes as well as a subset of messenger (m)RNA transcripts. The investigation of the dynamic composition of NEAT1-associated proteins and mRNAs is critical to understand the function of NEAT1. Interestingly, a growing number of biochemical and genetic tools to assess NEAT1 interactomes has been reported. Here, we discuss the Hybridisation Proximity (HyPro) labeling technique in the context of NEAT1. HyPro labeling is a recently developed method to detect spatially ordered interactions of RNA-containing nuclear compartments in cultured human cells. After introducing NEAT1 and paraspeckles, we describe the advantages of the HyPro technology in the context of other methods to study RNA interactomes, and review the key findings in mapping NEAT1-associated RNA transcripts and protein binding partners. We further discuss the limitations and potential improvements of HyPro labeling, and conclude by delineating its applicability in paraspeckles-related cancer research.

Socioeconomic origin, future expectations, and educational achievement: A longitudinal three-generation study of the persistence of family advantage.

Expectations about the future direct effort in goal-oriented action and may influence a range of life course outcomes, including educational attainment. Here we investigate whether such expectations are implicated in the dynamics underlying the persistence of educational advantage across family generations, and whether such dynamics have changed in recent decades in view of historical change. Focusing on the role of domain-specific (educational) and general (optimism and control) expectations, we examine parallels across parent-child cohorts in (a) the relationships between parental socioeconomic status (SES) and children's future expectations and (b) the associations between children's future expectations and their academic achievement. We estimate structural equation models using data from the prospective multigenerational Youth Development Study (N = 422 three-generation triads [G1-G2-G3]; G1 Mage in 1988 = 41.0 years, G2 Mage in 1989 = 14.7 years, G3 Mage in 2011 = 15.8 years; G2 White in 1989 = 66.4%, G3 White in 2011 = 64.4%; G1 mean annual household income, converted to 2008 equivalents = $41,687, G2 mean annual household income in 2008 dollars = $42,962; G1 mode of educational attainment = high school, G2 mode of educational attainment = some college). We find intergenerational similarity in the relationships between parental educational attainment and children's future expectations. Children's educational expectations strongly predicted their academic achievement in the second generation, but not in the third generation. With educational expansion, the more recent cohort had higher educational expectations that were less strongly related to achievement. Overall, the findings reveal dynamics underlying the persistence of educational success across generations. The role of future expectations in this intergenerational process varies across historical time, confirming a central conclusion of life span developmental psychology and life course sociological research that individual functioning is influenced by sociocultural contexts. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Commuting to Work: Nucleolar Long Non-Coding RNA Control Ribosome Biogenesis from Near and Far.

Gene expression is an essential process for cellular growth, proliferation, and differentiation. The transcription of protein-coding genes and non-coding loci depends on RNA polymerases. Interestingly, numerous loci encode long non-coding (lnc)RNA transcripts that are transcribed by RNA polymerase II (RNAPII) and fine-tune the RNA metabolism. The nucleolus is a prime example of how different lncRNA species concomitantly regulate gene expression by facilitating the production and processing of ribosomal (r)RNA for ribosome biogenesis. Here, we summarise the current findings on how RNAPII influences nucleolar structure and function. We describe how RNAPII-dependent lncRNA can both promote nucleolar integrity and inhibit ribosomal (r)RNA synthesis by modulating the availability of rRNA synthesis factors in trans. Surprisingly, some lncRNA transcripts can directly originate from nucleolar loci and function in cis. The nucleolar intergenic spacer (IGS), for example, encodes nucleolar transcripts that counteract spurious rRNA synthesis in unperturbed cells. In response to DNA damage, RNAPII-dependent lncRNA originates directly at broken ribosomal (r)DNA loci and is processed into small ncRNA, possibly to modulate DNA repair. Thus, lncRNA-mediated regulation of nucleolar biology occurs by several modes of action and is more direct than anticipated, pointing to an intimate crosstalk of RNA metabolic events.

Making it against the odds: How individual and parental co-agency predict educational mobility.

INTRODUCTION: This study examines the role of individual agency and parental co-agency as resource factors enabling educational mobility (university enrolment and degree completion) among first-generation students. METHODS: The study is based on Next Steps, a nationally representative cohort of UK students. Path models were run, linking different dimensions of agency assessed at age 13/14 to educational attainment by age 25/26, controlling for academic attainment and socio-demographic factors. RESULTS: Educational mobility was predicted by student's expectation to go to university, their expectation of success, and school engagement during secondary school. In addition, parental co-agency played a significant role - highlighting the importance of parents in supporting upward educational mobility of their children. CONCLUSIONS: Multiple dimensions of agency are necessary for disadvantaged students to achieve academically. To support first-generation students, schools need to provide opportunities for them to become engaged in education, to experience mastery and to develop realistic expectations of success.

Incongruence between parental and adolescent educational aspirations hinders academic attainment.

Previous research has shown that parental educational aspirations for their children are an important predictor of children's academic attainment. However, recent studies have pointed to potential negative effects, in particular if there is a mismatch between parental educational aspirations and the aspirations of their children. This study examines (1) the role of socio-demographic and school achievement-related factors in shaping a potential (mis)match between parental educational aspirations and the aspirations of their children, and (2) whether incongruence between parental and their children's educational aspirations hinders academic attainment in times of social change. We use data collected for the 1970 British Birth Cohort Study (BCS70) and Next Steps (formerly known as the Longitudinal Study of Young People in England), a cohort of young people born in 1989/90. We find that in both cohorts socio-demographic and achievement-related characteristics are associated with incongruent aspirations, and that incongruent aspirations between parents and their children are associated with a decreased likelihood of participating in and completing higher education. The study contributes to current debates regarding the causes and correlates of discrepancies in educational aspirations and how such discrepancies affect later life chances.

Self-esteem and self-efficacy in the status attainment process and the multigenerational transmission of advantage.

Despite considerable evidence of the importance of self-esteem and self-efficacy for agentic, goal-oriented behavior, little attention has been directed to these psychological dimensions in the status attainment literature. The present research uses data from the longitudinal, three-generation Youth Development Study (N = 422 three-generation triads) to examine the extent to which adolescent self-esteem and economic self-efficacy affect adult educational and income attainment, and whether these psychological resources are transmitted from one generation to the next, accumulating advantage across generations. We present evidence indicating that both self-esteem and economic self-efficacy are implicated in the attainment process. Adolescent economic self-efficacy had a direct positive effect on adult educational attainment and an indirect effect through educational plans. The influence of self-esteem on adult educational attainment was entirely indirect, through school achievement. We also find evidence that economic self-efficacy was transmitted from parents to children. We conclude that future research should more broadly consider psychological resources in attainment processes from a longitudinal multigenerational perspective.

Beyond the Trinity of ATM, ATR, and DNA-PK: Multiple Kinases Shape the DNA Damage Response in Concert With RNA Metabolism.

Our genome is constantly exposed to endogenous and exogenous sources of DNA damage resulting in various alterations of the genetic code. DNA double-strand breaks (DSBs) are considered one of the most cytotoxic lesions. Several types of repair pathways act to repair DNA damage and maintain genome stability. In the canonical DNA damage response (DDR) DSBs are recognized by the sensing kinases Ataxia-telangiectasia mutated (ATM), Ataxia-telangiectasia and Rad3-related (ATR), and DNA-dependent protein kinase (DNA-PK), which initiate a cascade of kinase-dependent amplification steps known as DSB signaling. Recent evidence suggests that efficient recognition and repair of DSBs relies on the transcription and processing of non-coding (nc)RNA molecules by RNA polymerase II (RNAPII) and the RNA interference (RNAi) factors Drosha and Dicer. Multiple kinases influence the phosphorylation status of both the RNAPII carboxy-terminal domain (CTD) and Dicer in order to regulate RNA-dependent DSBs repair. The importance of kinase signaling and RNA processing in the DDR is highlighted by the regulation of p53-binding protein (53BP1), a key regulator of DSB repair pathway choice between homologous recombination (HR) and non-homologous end joining (NHEJ). Additionally, emerging evidence suggests that RNA metabolic enzymes also play a role in the repair of other types of DNA damage, including the DDR to ultraviolet radiation (UVR). RNAi factors are also substrates for mitogen-activated protein kinase (MAPK) signaling and mediate the turnover of ncRNA during nucleotide excision repair (NER) in response to UVR. Here, we review kinase-dependent phosphorylation events on RNAPII, Drosha and Dicer, and 53BP1 that modulate the key steps of the DDR to DSBs and UVR, suggesting an intimate link between the DDR and RNA metabolism.

Tyrosine kinase c-Abl couples RNA polymerase II transcription to DNA double-strand breaks.

DNA is constantly exposed to endogenous and exogenous damage. Various types of DNA repair counteract highly toxic DNA double-strand breaks (DSBs) to maintain genome stability. Recent findings suggest that the human DNA damage response (DDR) utilizes small RNA species, which are produced as long non-coding (nc)RNA precursors and promote recognition of DSBs. However, regulatory principles that control production of such transcripts remain largely elusive. Here we show that the Abelson tyrosine kinase c-Abl/ABL1 causes formation of RNA polymerase II (RNAPII) foci, predominantly phosphorylated at carboxy-terminal domain (CTD) residue Tyr1, at DSBs. CTD Tyr1-phosphorylated RNAPII (CTD Y1P) synthetizes strand-specific, damage-responsive transcripts (DARTs), which trigger formation of double-stranded (ds)RNA intermediates via DNA-RNA hybrid intermediates to promote recruitment of p53-binding protein 1 (53BP1) and Mediator of DNA damage checkpoint 1 (MDC1) to endogenous DSBs. Interference with transcription, c-Abl activity, DNA-RNA hybrid formation or dsRNA processing impairs CTD Y1P foci formation, attenuates DART synthesis and delays recruitment of DDR factors and DSB signalling. Collectively, our data provide novel insight in RNA-dependent DDR by coupling DSB-induced c-Abl activity on RNAPII to generate DARTs for consequent DSB recognition.

The subjective importance of children's participation rights: A discrimination perspective.

This study examined how children appraise the importance of their participation rights-that is, the right to express their views and the right to be heard-and whether such appraisals vary as a function of perceived discrimination in the school environment. The sample comprised 1,006 children (9.6-14.3 years of age; 51% boys) from 14 public primary schools in Geneva, Switzerland. Results indicate that a majority of children considered their participation rights as very important. Children's appraisals of these rights varied marginally between classes and schools. Moreover, children's individual-level appraisals were sensitive to their perceptions of discrimination in the school environment, in that higher levels of perceived discrimination were associated with a greater subjective importance attached to participation rights. This suggests that appropriate measures must be taken to implement participation rights in such a manner that all children-including those who feel discriminated against-will be protected by, and fully able to enjoy, their participation rights. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Nuclear re-localization of Dicer in primary mouse embryonic fibroblast nuclei following DNA damage.

Dicer is a key component of RNA interference (RNAi) and well-known for its role in biogenesis of micro (mi)RNA in the cytoplasm. Increasing evidence suggests that mammalian Dicer is also present and active in the nucleus. We have previously shown that phosphorylated human Dicer associates with chromatin in response to DNA damage and processes double-stranded (ds)RNA in the nucleus. However, a recent study by Much et al. investigated endogenously tagged HA-Dicer both in primary mouse embryonic fibroblasts (PMEFs) as well as adult homozygous viable and fertile HA-Dicer mice under physiological conditions and concluded that murine Dicer is exclusively cytoplasmic. The authors challenged several findings, reporting functions of Dicer in mammalian nuclei. We have re-investigated this issue by applying subcellular fractionation, super-resolution microscopy followed by 3D reconstitution, and phospho-Dicer-specific antibodies using the same HA-Dicer PMEF cell line. Our data show that a small fraction of the murine HA-Dicer pool, approximately 5%, localises in the nucleus and is phosphorylated upon DNA damage. We propose that Dicer localisation is dynamic and not exclusively cytoplasmic, particularly in cells exposed to DNA damage.