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Abstract Base excision repair is the main pathway involved in active DNA demethylation. 5-formylcytosine and 5-carboxylcytosine, two oxidized moieties of methylated cytosine, are recognized and removed by thymine DNA glycosylase (TDG) to generate an abasic site. Using single molecule fluorescence experiments, we study TDG in the presence and absence of 5-formylcytosine. TDG exhibits multiple modes of linear diffusion, including hopping and sliding, in search of base modifications. TDG active site variants and truncated N-terminus, reveals these variants alter base modification search and recognition mechanism of TDG. On DNA containing an undamaged nucleosome, TDG is found to either bypass, colocalize with, or encounter but not bypass the nucleosome. Truncating the N-terminus reduces the number of interactions with the nucleosome. Our findings provide mechanistic insights into how TDG searches for modified DNA bases in chromatin.

Abstract Clinical success with poly (ADP-ribose) polymerase inhibitors (PARPi) is impeded by inevitable resistance and associated cytotoxicity. Depletion of Amplified in Liver Cancer 1 (ALC1), a chromatin-remodeling enzyme, can overcome these limitations by hypersensitizing BReast CAncer genes 1/2 (BRCA1/2) mutant cells to PARPi. Here, we demonstrate that PARPi hypersensitivity upon ALC1 loss is reliant on its role in promoting the repair of chromatin buried abasic sites. We show that ALC1 enhances the ability of the abasic site processing enzyme, Apurinic/Apyrimidinic endonuclease 1 (APE1) to cleave nucleosome-occluded abasic sites. However, unrepaired abasic sites in ALC1-deficient cells are readily accessed by APE1 at the nucleosome-free replication forks. APE1 cleavage leads to fork breakage and trapping of PARP1/2 upon PARPi treatment, resulting in hypersensitivity. Collectively, our studies reveal how cells overcome the chromatin barrier to repair abasic lesions and uncover cleavage of abasic sites as a mechanism to overcome limitations of PARPi.

Antiretroviral APOBEC3 may contribute to HIV-1 latency. In this study, Ajoge and Renner et al. identify a previously undescribed function of human APOBEC3 proteins in redirecting integrations of HIV-1 DNA into more transcriptionally inactive regions of the genome.

Diagnosis of bile duct cancer often occur in advanced stages, leading to poor survival. Here, the authors combine light scattering and diffuse reflectance spectroscopies in a minimally invasive endoscopic technique for directly assessing the malignant potential of the bile duct lining, and demonstrate 97% detection accuracy.

AP endonuclease 1 (APE1) processes genomic AP sites during base excision repair. Here, the authors determine the structural mechanism used by APE1 to process nucleosomal AP sites, providing new insight into DNA repair in chromatin.

Rev1 is a specialized translesion synthesis DNA polymerase involved in the bypass DNA damage during DNA replication. Here, the authors determine the structural basis for preferential incorporation of dCTP by Rev1 during bypass of DNA damage.

Studies of brain network development typically focus on a single scale. Here, the authors derived personalized functional networks across scales, and find that network development systematically adheres to and strengthens hierarchical cortical organization.

A polygenic hazard score (PHS1) improves prostate cancer screening accuracy in European patients. Here, the authors test the performance of a version compatible with OncoArray genotypes (PHS2) in a multi-ethnic dataset and find that it risk-stratifies men for any, aggressive, and fatal prostate cancer.

Co-morbidity and symptom overlap make it difficult to associate psychiatric disorders with unique neural signatures. Here, the authors use a data-driven approach to show that the symptom dimensions of mood, psychosis, fear and externalizing behavior exhibit unique patterns of functional dysconnectivity.

Human brain development is characterized by an increased control of neural activity, but how this happens is not well understood. Here, authors show that white matter connectivity in 882 youth, aged 8-22, becomes increasingly specialized locally and is optimized for network control.

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p

Clinical success with poly (ADP-ribose) polymerase inhibitors (PARPi) is impeded by inevitable resistance and associated cytotoxicity. Depletion of Amplified in Liver Cancer 1 (ALC1), a chromatin-remodeling enzyme, can overcome these limitations by hypersensitizing BReast CAncer genes 1/2 (BRCA1/2) mutant cells to PARPi. Here, we demonstrate that PARPi hypersensitivity upon ALC1 loss is reliant on its role in promoting the repair of chromatin buried abasic sites. We show that ALC1 enhances the ability of the abasic site processing enzyme, Apurinic/Apyrimidinic endonuclease 1 (APE1) to cleave nucleosome-occluded abasic sites. However, unrepaired abasic sites in ALC1-deficient cells are readily accessed by APE1 at the nucleosome-free replication forks. APE1 cleavage leads to fork breakage and trapping of PARP1/2 upon PARPi treatment, resulting in hypersensitivity. Collectively, our studies reveal how cells overcome the chromatin barrier to repair abasic lesions and uncover cleavage of abasic sites as a mechanism to overcome limitations of PARPi. Loss of Amplified in Liver Cancer 1 (ALC1) has been shown to confer PARP inhibitor hypersensitivity in BRCA-mutant cells. Here, the authors show that in ALC1-deficient BRCA-mutant cells, APE1 cleaves abasic sites at the forks resulting in DNA breaks and thereby enhances PARP inhibitor sensitivity. [ABSTRACT FROM AUTHOR]

Abstract The human infectious reservoir of Plasmodium falciparum is governed by transmission efficiency during vector-human contact and mosquito biting preferences. Understanding biting bias in a natural setting can help target interventions to interrupt transmission. In a 15-month cohort in western Kenya, we detected P. falciparum in indoor-resting Anopheles and human blood samples by qPCR and matched mosquito bloodmeals to cohort participants using short-tandem repeat genotyping. Using risk factor analyses and discrete choice models, we assessed mosquito biting behavior with respect to parasite transmission. Biting was highly unequal; 20% of people received 86% of bites. Biting rates were higher on males (biting rate ratio (BRR): 1.68; CI: 1.28–2.19), children 5–15 years (BRR: 1.49; CI: 1.13–1.98), and P. falciparum-infected individuals (BRR: 1.25; CI: 1.01–1.55). In aggregate, P. falciparum-infected school-age (5–15 years) boys accounted for 50% of bites potentially leading to onward transmission and had an entomological inoculation rate 6.4x higher than any other group. Additionally, infectious mosquitoes were nearly 3x more likely than non-infectious mosquitoes to bite P. falciparum-infected individuals (relative risk ratio 2.76, 95% CI 1.65–4.61). Thus, persistent P. falciparum transmission was characterized by disproportionate onward transmission from school-age boys and by the preference of infected mosquitoes to feed upon infected people.

Abstract The multi-cohort phase 2 trial NCT02203513 was designed to evaluate the clinical activity of the CHK1 inhibitor (CHK1i) prexasertib in patients with breast or ovarian cancer. Here we report the activity of CHK1i in platinum-resistant high-grade serous ovarian carcinoma (HGSOC) with measurable and biopsiable disease (cohort 5), or without biopsiable disease (cohort 6). The primary endpoint was objective response rate (ORR). Secondary outcomes were safety and progression-free survival (PFS). 49 heavily pretreated patients were enrolled (24 in cohort 5, 25 in cohort 6). Among the 39 RECISTv1.1-evaluable patients, ORR was 33.3% in cohort 5 and 28.6% in cohort 6. Primary endpoint was not evaluable due to early stop of the trial. The median PFS was 4 months in cohort 5 and 6 months in cohort 6. Toxicity was manageable. Translational research was an exploratory endpoint. Potential biomarkers were investigated using pre-treatment fresh biopsies and serial blood samples. Transcriptomic analysis revealed high levels of DNA replication-related genes (POLA1, POLE, GINS3) associated with lack of clinical benefit [defined post-hoc as PFS

Recent studies proposed that m6A modification in mammalian mRNAs increases their recruitment to stress granule. However, here the authors observed that m6A modification has a limited effect on mRNA entry into stress granules.

The endoplasmic reticulum-localized adaptor STING regulates the innate immune response through its ability to sense DNA damage. Here the authors reveal that STING functions as a regulator of cellular ROS homeostasis and tumor cell susceptibility to reactive oxygen dependent, DNA damaging agents.

Obesity and its associated metabolic changes, including hyperinsulinemia and aberrant circadian rhythms, increases the risk for a variety of cancers including postmenopausal breast cancer. Here, the authors show that restricting when mice eat, but not what or how much they eat, delays breast cancer initiation and reduces tumor growth in obese mice in addition to improving insulin sensitivity and restoring circadian rhythms.

Sex and the APOE ε4 genotype are important risk factors for late-onset Alzheimer’s disease. In the current study, the authors investigate how sex and APOE ε4 genotype modify the association between Alzheimer’s disease biomarkers and metabolites in serum.

Many RNA systems possess highly ordered 3-D structures that are essential to their function. Here the authors demonstrate that the long non-coding RNA Braveheart possesses a flexible but defined 3-D structure which is remodeled upon binding the protein CNBP.

UDP-glucuronic acid is a component of the extracellular matrix. Here, the authors report biallelic variants in the gene encoding UDP-Glucose 6-Dehydrogenase (UGDH) in individuals affected by developmental epileptic encephalopathies that impair UGDH stability, oligomerization, or enzymatic activity in vitro.

Lithium metal is an ideal anode material for rechargeable batteries but suffer from the growth of lithium dendrites and low Coulombic efficiency. Here the authors show that nanodiamonds serve as an electrolyte additive to co-deposit with lithium metal and suppress the formation of dendrites.

Epithelial-to-mesenchymal transition (EMT) is the most commonly cited mechanism for cancer metastasis, but it is difficult to distinguish from profiles of normal stromal cells in the tumour microenvironment. In this study we use published single cell RNA-seq data to directly compare mesenchymal signatures from cancer and stromal cells. Informed by these comparisons, we developed a computational framework to decouple these two sources of mesenchymal expression profiles using bulk RNA-seq datasets. This deconvolution offers the opportunity to characterise EMT across hundreds of tumours and examine its association with metastasis and other clinical features. With this approach, we find three distinct patterns of EMT, associated with squamous, gynaecological and gastrointestinal cancer types. Surprisingly, in most cancer types, EMT patterns are not associated with increased chance of metastasis, suggesting that other steps in the metastatic cascade may represent the main bottleneck. This work provides a comprehensive evaluation of EMT profiles and their functional significance across hundreds of tumours while circumventing the confounding effect of stromal cells.