Biology subjects

Ing, A.

Publications and source records attributed to Ing, A..

4 recordsLinked to original sources

bioRxiv2026

An integrated genome-wide resource reveals distinct replication environments of DNA breakage in human cancer cell lines

Replication stress is a major source of genome instability in cancer, yet the genomic features that determine where DNA double-strand breaks (DSBs) arise remain incompletely defined. Here, we establish an integrated genome-wide resource of DSBs, DNA replication, replication timing, transcription, and R-loops in two widely used cancer cell lines, U2-OS and HeLa, under steady-state conditions and following prolonged low-dose DNA polymerase inhibition. We combine these datasets with systematic statistical testing and comparative analytical approaches to define the replication environments associated with genome fragility. Endogenous DSBs preferentially accumulated at origin-rich initiation zones, where R-loops were enriched, whereas prolonged DNA polymerase inhibition redirected DSB formation toward origin-poor, late-replicating regions. Among the replication features examined, replication initiation zones and late-replicating areas were most sensitive to prolonged replication stress. R-loops were specifically enriched at initiation zones but depleted from late-replicating regions and recurrent DNA break clusters (RDCs), demonstrating that their association with genome fragility is context dependent. Replication stress further induced RDCs within long, actively transcribed genes, while their locations only partially overlapped with common fragile sites. Functional analyses identified MUS81 as a major regulator of RDC formation. MUS81 loss increased RDCs, whereas restoration of its catalytic activity suppressed them, indicating that MUS81 resolves replication intermediates before they persist into late-replicating fragile regions. Together, this resource and analytical framework provide a systematic basis for dissecting how replication architecture, transcription, and DNA processing shape genome fragility in cancer cells.

genomics↗

bioRxiv2025

Recurrent DNA Break Clusters Regulated by Polymerase Theta Are Essential for Replication Stress Induced Copy Number Variation

Copy number variations (CNVs) are a form of genetic alteration strongly implicated in numerous neurological and psychiatric disorders, as well as brain cancer. Replication stress is a common cause of CNVs. Despite the prevailing model that CNVs arise from DNA double strand breaks (DSBs), there has been no assay that directly perturbs presumed DSB sources and measures CNV output. Here, we identified a subset of recurrent DNA break clusters (RDCs) as a causal factor for CNV formation. In murine neural progenitor cells under replication stress, mapping the formation of CNVs revealed their location in RDC regions that contain actively transcribed genes. CRISPR/Cas9-mediated transcriptional suppression abrogated both RDC and CNV formation, but does not alter their replication timing. We found that DNA polymerase theta (Pol {theta}), a protector against CNV formation, plays a critical but context dependent role upstream of RDC formation. Chemically inhibiting the activity of Pol {theta} reduced end filling and micro-homology-mediated end joining in XRCC4/P53-deficient cells. Conversely, Pol {theta} inhibition led to elevated DSB density detection at RDC-containing loci in wild-type neural stem and progenitor cells, suggesting its role in preventing transcription-replication conflicts. Our data identify RDCs as contributors to genomic heterogeneity with plausible downstream effects on brain disorders and malignancy.

molecular biology↗

bioRxiv2019

Satellite Imaging of Global Urbanicity relate to Adolescent Brain Development and Behavior

Urbanicity, the impact of living in urban areas, is among the greatest environmental challenges for mental health. While urbanicity might be distinct in different sociocultural conditions and geographic locations, there are likely to exist common features shared in different areas of the globe. Understanding these common and specific relations of urbanicity with human brain and behavior will enable to assess the impact of urbanicity on mental disorders, especially in childhood and adolescence, where prevention and early interventions are likely to be most effective.\n\nWe constructed from satellite-based remote sensing data a factor for urbanicity that was highly correlated with population density ground data. This factor, UrbanSat was utilized in the Chinese CHIMGEN sample (N=831) and the longitudinal European IMAGEN cohort (N=810) to investigate if exposure to urbanicity during childhood and adolescence is associated with differences in brain structure and function in young adults, and if these changes are linked to behavior.\n\nUrbanicity was found negatively correlated with medial prefrontal cortex volume and positively correlated with cerebellar vermis volume in young adults from both China and Europe. We found an increased correlation of urbanicity with functional network connectivity within- and between- brain networks in Chinese compared to European participants. Urbanicity was highly correlated with a measure of perceiving a situation from the perspective of others, as well as symptoms of depression in both datasets. These correlations were mediated by the structural and functional brain changes observed. Susceptibility to urbanicity was greatest in two developmental windows during mid-childhood and adolescence.\n\nUsing innovative technology, we were able to probe the relationship between urban upbringing with brain change and behavior in different sociocultural conditions and geographic locations. Our findings help to identify shared and distinct determinants of adolescent brain development and mental health in different regions of the world, thus contributing to targeted prevention and early-intervention programs for young people in their unique environment. Our approach may be relevant for public health, policy and urban planning globally.

neuroscience↗

bioRxiv2019

Neurobehavioural characterisation and stratification of reinforcement-related behaviour

AbstractReinforcement-related cognitive processes, such as reward processing, impulsiveness and emotional processing are critical components of externalising and internalising behaviours. It is unclear to what extent each of these processes contributes to individual behavioural symptoms, how their neural substrates give rise to distinct behavioural outcomes, and if neural profiles across different reinforcement-related processes might differentiate individual behaviours. We created a statistical framework that enabled us to directly compare functional brain activation during reward anticipation, motor inhibition and viewing of emotional faces in the European IMAGEN cohort of 2000 14-year-old adolescents. We observe significant correlations and modulation of reward anticipation and motor inhibition networks in hyperactivity, impulsivity, inattention and conduct symptoms, and describe neural signatures across neuroimaging tasks that differentiate these behaviours. We thus characterise shared and distinct functional brain activation patterns that underlie different externalising symptoms and identify neural stratification markers, while accounting for clinically observed co-morbidity.

neuroscience↗