BRCA1-deficient tumors are hypersensitive to PARP inhibitors (PARPi) due to impaired homologous recombination (HR). The 53BP1-Shieldin complex inhibits end resection at replication-independent DNA double-strand breaks (DSBs), promoting PARPi sensitivity in BRCA1-deficient cells. However, its role in replication-coupled DSBs is less clear. Here, we show that loss of Shld2 or Shld3, but not 53bp1, confers PARPi resistance in mouse embryonic stem cells lacking a functional BRCA1 BRCT domain. Unlike 53bp1 loss, deletion of Shld2 or Shld3 partially restores HR at replication-coupled DSBs, reduces BRCA1-linked insertion/deletion signatures, and promotes RAD51 loading. This 53BP1-independent function requires the CST complex and counteracts residual BRCA1 coiled-coil domain activity in RAD51 loading. Shld2 loss also confers PARPi resistance in Bard1-null cells retaining residual BRCA1, but not in cells expressing RING-less BRCA1 with degraded BARD1. These findings identify a 53BP1-independent

A subpopulation of EMC was found to cofractionate through a sucrose gradient with Sec61-associated ribosomes prepared from nuclease-treated, digitonin-solubilized human embryonic kidney 293 (HEK293) membranes (Extended Data Fig. 1). To identify the proteins being synthesized on EMC-engaged ribosomes, we affinity purified these complexes via tagged EMC subunits and sequenced the ribosome-protected messenger RNA (mRNA) fragments30,31. The EMC-selective sequencing data, obtained using HEK293 cell lines stably expressing Flag-tagged EMC6, EMC7 and EMC10, were compared to matched ribosome-protected mRNA sequences obtained from total membranes. As expected for subunits of the same complex, transcript enrichment was highly correlated for EMC6, EMC7 and EMC10, allowing us to combine the datasets into a single sample (n = 7), hereafter referred to as ‘EMC’ (Extended Data Fig. 2). Of the ~5,800 proteins detected in the combined EMC dataset, multipass proteins were the most enriched class, with 38% of type I, 62% of type II and 57% of type III multipass proteins showing log2 enrichment ≥2 (Fig. 1a). In contrast to MPT, shown previously to enrich most multipass proteins regardless of TMD number12, EMC recovered only a subset, with enrichment increasing with the number of TMDs (Fig. 1b,c). Comparison of the EMC and MPT datasets showed that...

Operation Vivaldi has seen Ukraine make progress against Russian forces, which had been threatening a key fortress city.

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KYIV — Ukraine’s army pushed back Russian forces in a key part of the eastern front with Russia and captured more than 250 prisoners, a senior Ukrainian general announced on Monday. "Russians surrendered by entire subunits, along with officers, pilots, and artillerymen," said Gen. Andrii Biletskyi, commander of the Third Army Corps. He said the success was the third part of Operation Vivaldi, a carefully prepared effort to recapture the initiative in the Donetsk region. The latest phase recaptured 51 square kilometers of territory, bringing the total recovered during Vivaldi to 176 square kilometers, according to the Third Army Corps. The operation shows that Ukraine can reuse some Russian advances. It also has significance beyond the battlefield: Kyiv sees such counterattacks as evidence to its allies — and particularly the Trump administration — that Russia's grinding advances in Donetsk are not inevitable and that Russian leader Vladimir Putin cannot simply wait for Ukraine's defenses and Western resolve to collapse. Vivaldi has seen the integrated use of drones, armor, artillery and infantry against Russian forces attempting a pincer attack to seize control of Lyman, a lynchpin of the "fortress belt" cities that have stymied Russian advances for years. "Russian forces had...

Pathogenic variants in the 13 protein-coding genes of the mitochondrial genome underlie clinically and biochemically heterogeneous disorders. Most mtDNA-encoded genes lack defined loss-of-function (LOF) models in vivo. To address this gap, we have generated Z-Terminator, a systematic in vivo atlas of loss-of-function alleles covering all the mtDNA-encoded OXPHOS subunits in zebrafish (Danio rerio). We used mitochondrial TALE base editors to introduce premature termination codon (PTC) alleles via...

A cell's ability to repair its damaged DNA is one of the most fundamental processes in biology, helping protect us from diseases like cancer.

TRranscription EXport (TREX) is an evolutionarily conserved multifunctional complex with essential roles in regulating transcription, mRNA export, gen…

Ferritin, composed of heavy chain (FTH1) and light chain (FTL) subunits, is a key intracellular iron storage protein, but the origin and biological role of extracellular ferritin (ex-ferritin) remain poorly understood. Elevated serum ex-ferritin is associated with worse outcomes in acute respiratory distress syndrome (ARDS). Here, we show that both FTH1 and FTL are significantly enriched in the serum, blood monocytes, and alveolar macrophages (AM) of individuals with ARDS, findings we replicate in a murine hyperoxia-induced acute lung injury model. Myeloid-specific FTH1 (Fth1ΔLysM) deletion attenuates lung injury, and is associated with reduced macrophage ferroptosis, altered airway inflammatory responses, lower extracellular iron and compensatory secretion of FTL-ex-ferritin. While pharmacologic ferroptosis inhibition prior to hyperoxia had no effect, transplantation of FTL-ex-ferritin-enriched bronchoalveolar lavage fluid conferred protection from lung injury. These findings identify

Successive maturation of ribosomal subunits occurs through multilayered phase-separated structures of the cell nucleolus. The spatio-functional relationship between transcription of rRNA and nucleolar...

Members of the LRRC8 family form heteromeric ion channels that are activated upon cell swelling. Here authors describe the architecture of assemblies of LRRC8A and D subunits and their conformational changes during activation.

AMPA receptors mediate the majority of excitatory neurotransmission. Here, the authors report structural and functional regulation of GluA2 AMPA receptor by inhibitory auxiliary subunits GSG1L and TARP γ5 and by epilepsy-associated disease mutations.