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Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

Alternative lengthening of telomeres in cancer cells is initiated by a specialized replisome and noncanonical homologous recombination at damaged telomeres, culminating in the synthesis of long tracts of telomere DNA.

Ni, Wei, Vona and colleagues use human brain organoids to dissect patient AIRIM variants associated with neurodevelopmental features. A subset of variants impaired ribosome production and protein synthesis, and delayed radial glial cell specification.

The authors report a link between mitosis, the formation of micronuclei and DNA-damage-induced cGAS-dependent inflammation.

The BRCC36 isopeptidase complex (BRISC) is a deubiquitylase that stabilizes interferon receptors, driving inflammation. We discovered ‘BRISC molecular glue’ inhibitors (BLUEs) that selectively inactivate BRISC, promoting interferon receptor ubiquitylation and degradation to dampen immune responses.

Break-induced telomere synthesis initiates recruitment of the SNM1A nuclease, which promotes DNA end resection that in turn allows template switching to enable bypass of lesions.

The CHAMP1 complex, consisting of CHAMP1, POGZ, and HP1α, is enriched in heterochromatin, but its role was unclear. Here, the authors demonstrate that the CHAMP1 complex promotes heterochromatin assembly and homology-directed repair, with its dysfunction linked to CHAMP1 syndrome.

Ovarian and endometrial cancers with CCNE1-amplification are often resistant to standard treatment. Here, the authors identify that CCNE1-amplified gynecological cancer is sensitive to combined PKMYT1 and ATR inhibition via CDK1 activation, resulting in premature mitosis, DNA damage, cell apoptosis and reduced tumour growth and metastasis.

Absorption features in Io's reflectance spectrum suggest that frozen SO₂ molecules are present on the surface of Io as free frost; this may have important implications for Io's atmosphere.

Variants of the 3′−5′ exonuclease TREX1 can cause retinal vasculopathy with cerebral leukoencephalopathy (RVCL). Here, the authors show that RVCL-associated TREX1 variants trigger DNA damage in humans, mice, and Drosophila, and render cells more vulnerable to DNA damage inducing agents.

An international consortium reports the genomic sequence for ten Drosophila species, and compares them to two other previously published Drosophila species. These data are invaluable for drawing evolutionary conclusions across an entire phylogeny of species at once.

The DCAF15 E3 ubiquitin ligase is targeted by aryl-sulfonamide molecular glues leading to neo-substrate proteasomal degradation. Here, the authors reveal DCAF15 as a cell autonomous acute myeloid leukemia dependency sustaining proliferation through control of cohesin complex recycling dynamics.

Cryo-electron microscopy and mutation experiments demonstrate that the inactive SHMT2 dimer—and not the pyridoxal-5′-phosphate-bound tetramer—binds to BRISC, which reveals a mechanism for the regulation of deubiquitylases and inflammatory signalling.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

Chromium tellurides are a particularly promising family of quasi-2D magnetic materials; towards the single van der Waals layer limit, they preserve magnetic ordering, some even above room temperature, and exhibit a variety of intrinsic topological properties. Here, Hang Chi, Yunbo Ou and co-authors demonstrate a strain tunable Berry curvature induced reversal of the anomalous Hall effect in Cr₂Te₃.

Pheochromocytomas and paragangliomas (PCC/PGL) are tumours of the autonomic nervous system. Here, the authors identify ATRX mutations in PCC/PGL and suggest that ATRXloss is important for tumorigenesis in a subset of PCC/PGL.

Verma et al. report that ALC1 loss confers PARP inhibitor hypersensitivity in homologous recombination-deficient cells through reducing chromatin accessibility.

Patients with ovarium cancer frequently develop resistance to platinum chemotherapy and PARP inhibitors (PARPi). Here, the authors show that the combination of PARP and ATR inhibitors increases the therapeutic response in PARPi and platinum resistant ovarium cancer PDX models.

The faithful propagation of species requires a complex balance of DNA-repair pathways to maintain genome integrity. New work sheds light on one such poorly understood pathway and its role in certain cancers. See Letters p.254 & p.258

Break-induced replication (BIR) is a crucial DNA double-strand break-repair pathway, but it also introduces mutations linked to cancer and genetic disorders. This Review discusses BIR regulation in mammalian cells, its roles in human disease and its potential uses in genome engineering.

Loss of Fancd2 leads to replication stress intolerance and Fanconi Anemia, where haematopoietic stem cell (HSC) function is compromised. Here, the authors show that Lnk/Sh2b3 loss restores HSC proliferation and survival in Fancd2 knockout mice and ameliorates replication stress in a cytokine/JAK2 signaling dependent manner.

A CRISPR screen in mouse embryonic stem cells shows that transcripts derived from endogenous retroviruses are destabilized by m⁶A RNA methylation.

Competitive binding of 53BP1 and BRCA1 determines DNA repair pathway choice at double-strand breaks. New work shows that acetylation of H4K16 by TIP60 tips the balance in favor of BRCA1 by limiting 53BP1 binding, thereby promoting repair through homologous recombination over nonhomologous end joining.

Poly(ADP-ribose) polymerase-1 (PARP-1) facilitates local chromatin relaxation and the recruitment of DNA repair factors at double strand breaks site (DSBs). Here the authors reveal that PARP-1 acts as a critical regulator of DNA end resection of DSBs.

Measurement of in vivo neuronal activity with single neuron and single action potential resolution is important for studying neuronal function. Delivery of a FRET-based fluorescent Ca²⁺ indicator protein using adeno-associated virus results in high expression levels allowing in vivo detection of single action potentials at low firing rates. Griesbeck et al., also in this issue, describe the use of a similar sensor for recording neuronal activity in vivo.

Development of the bright green and red fluorescent proteins, Clover and mRuby2, creates a fluorescence resonance energy transfer (FRET) pair with the highest Förster radius among existing ratiometric FRET pairs. Substitution of this pair for current FRET pairs in several existing sensors reliably and substantially improves sensor performance.

A previously unidentified protein complex termed Shieldin acts with the nucleosome-binding protein 53BP1 to limit end resection at DNA double-strand breaks, impacting myriad biological outcomes, from immunology to cancer therapy, and highlighting the importance of chromatin responses to DNA damage in vertebrates.