Molecular Cell

PALB2 and 53BP1 govern post-resection homologous recombination DNA repair Wang et al. demonstrate that the PALB2 CC domain has single-stranded (ss)DNA-binding activity that is essential for PALB2 and RAD51 to form DNA-damage foci. By creating Palb2 CC-mutated mice, they found that CC activity was required for development but could be partially rescued by removal of 53BP1.

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Nucleosomes specify co-factor access to p53 Chakraborty, Sandate, et al. report that chromatin-bound p53 interacts with deubiquitinating enzyme USP7 but not with the E3 ubiquitin ligase E6AP-E6, despite both co-factors being associated with the ubiquitin proteasome system that regulates p53 levels. This study highlights the critical role of chromatin in determining the interaction of p53 with its regulatory co-factors.

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Human mitochondrial RNA polymerase structures reveal transcription start site and slippage mechanism Shen et al. report biochemical and structural studies of transcription initiation by human mitochondrial RNA polymerase, POLRMT, with initiation factors TFAM and TFB2M. The catalytically competent structures provide the basis for normal and slippage RNA synthesis from the light strand promoter. The slippage synthesis occurs via 2-nt RNA sliding or reannealing.

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HIF-independent oxygen sensing via KDM6A regulates ferroptosis Minikes et al. define an HIF-independent oxygen-sensing mechanism that regulates ferroptotic death through modulating the phospholipidome. When oxygen is limited, the histone demethylase KDM6A is inactivated, rewiring the phospholipidome toward a ferroptosis-resistant state by downregulating ACLS4 and ETNK1. Inhibition of EZH2, an epigenetic regulator that counteracts KDM6A, renders otherwise insensitive KDM6A-mutant bladder tumors sensitive to ferroptosis.

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Enhancing transcriptome mapping with rapid PRO-seq profiling of nascent RNA Cingaram et al. present rPRO-seq, a rapid, low-input technique that enables nascent transcript profiling from as few as 5,000 cells. Using this method in neurons, they uncover a crucial role for INTS11 in regulating genes linked to neurodevelopmental disorders, advancing tools for transcriptome analysis in limited samples.

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Structural basis for promoter recognition and transcription factor binding and release in human mitochondria Herbine et al. reveal how human mitochondrial RNA polymerase and its partner factors coordinate transcription initiation. Structural snapshots capture key steps from promoter binding and melting to RNA synthesis, factor release, and TEFM recruitment, providing a detailed view of the transition from initiation to elongation in mitochondrial transcription.

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Single-molecule live imaging of subunit interactions and exchange within cellular regulatory complexes Graham et al. show that proximity-assisted photoactivation (PAPA) can visualize interactions of endogenous proteins at single-molecule resolution in live human cells. Applying PAPA to the P-TEFb regulatory network showed that the inhibited P-TEFb:7SK complex is largely unbound to chromatin and revealed subunit exchange within 7SK complexes upon Cdk9 inhibition.

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Phosphorylation of EZH2 by AMPK Suppresses PRC2 Methyltransferase Activity and Oncogenic Function (Molecular Cell 69, 279–291.e1–e5; January 18, 2018)

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β-catenin functions as a molecular adapter for disordered cBAF interactions By dissecting steroidogenic expression dependencies, Chan et al. reveal that β-catenin mediates physical association of cBAF with key binding partners. The authors show that a disordered region of cBAF subunit ARID1A interacts with Armadillo repeats on β-catenin, highlighting roles for modular adapters in IDR-mediated interactions.

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Structural mechanism of H3K27 demethylation and crosstalk with heterochromatin markers Chien-Chu Lin et al. reveal the structure of the histone demethylase KDM6B bound to the nucleosome. The study shows how KDM6B is positioned for H3K27 demethylation and how heterochromatin features such as H2AK119ub1 and linker histones antagonize KDM6B function.

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An allele of a hexameric enzyme is poised for an autoimmune dangerous mix In this issue of Molecular Cell, Wan et al. elucidate how incompatible genetic interactions between immune receptors and cellular homeostatic enzymes can lead to hybrid necrosis in the plant Arabidopsis thaliana. This suggests that the immune system can monitor cellular integrity via subtle structural changes in higher-order enzyme complexes.

An allele of a hexameric enzyme is poised for an autoimmune dangerous mix

m6A-induced ribosome stalling and collision trigger mRNA decay How m6A in different transcript regions regulates mRNA decay remains an intriguing question. Three studies from the labs of König, Jaffrey, and Steinmetz uncovered translation-dependent CDS-m6A decay: m6A in the coding sequence (CDS) induces ribosome stalling and collision to trigger mRNA decay, while tRNA modification alleviates the effects.

m6A-induced ribosome stalling and collision trigger mRNA decay

Monkey business: Primate Ku moonlights for the innate immune response Ku is associated with non-homologous end joining (NHEJ), a double-strand break repair pathway, in all kingdoms of life, but Zhu et al. find that it gains an essential function in human cells down-regulating innate immune responses.

Monkey business: Primate Ku moonlights for the innate immune response

Lactylation of XLF promotes non-homologous end-joining repair and chemoresistance in cancer Jin et al. show that lactate derived from glycolysis drives the lactylation of DNA repair protein XLF, enhancing its interaction with Ku and promoting non-homologous end-joining repair and chemoresistance.

Lactylation of XLF promotes non-homologous end-joining repair and chemoresistance in cancer

YTHDC1 lactylation regulates its phase separation to enhance target mRNA stability and promote RCC progression Dai et al. find that hypoxia induces protein hyperlactylation in renal cell carcinoma (RCC). p300-mediated YTHDC1 K82 lactylation promotes the expansion of phase-separated condensates. These condensates protect oncogenic BCL2 and E2F2 mRNAs from degradation by the PAXT complex to drive RCC progression.

YTHDC1 lactylation regulates its phase separation to enhance target mRNA stability and promote RCC progression

Structural determinants of DANGEROUS MIX 3, an alpha/beta hydrolase that triggers NLR-mediated genetic incompatibility in plants Wan, Kim, et al. provide cryo-EM structures of DANGEROUS MIX 3 (DM3) metabolic enzyme complexes from two Arabidopsis natural accessions, revealing an immune switch. Compromised DM3 dimer interface integrity triggers DM2h NLR activation and immune signaling in plants. This work suggests that enzyme complex surveillance leads to immune conflict in plants, resulting in autoimmune responses in hybrids.

Structural determinants of DANGEROUS MIX 3, an alpha/beta hydrolase that triggers NLR-mediated genetic incompatibility in plants

Chromatin architecture mapping by multiplex proximity tagging Delamarre et al. develop a technology named PCP that can simultaneously map complex spatial relationships between millions of molecules. Using PCP, they investigate chromatin structure and describe single-molecule nucleosome arrangements, multi-way 3D interactions in metaphase, and noncanonical nucleosome structures at gene promoters.

Chromatin architecture mapping by multiplex proximity tagging

Mechanism of cotranslational protein N-myristoylation in human cells In structure-function studies, Gamerdinger and Echeverria et al. uncover the cotranslational mechanism of N-myristoyltransferases (NMTs), essential enzymes that attach a lipid anchor to newborn proteins. They show that NMT activity is orchestrated by a key regulator at the ribosomal tunnel exit, the nascent polypeptide-associated complex (NAC).

Mechanism of cotranslational protein N-myristoylation in human cells

TRIM24 directs replicative stress responses to maintain ALT telomeres via chromatin signaling Kim et al. develop BLOCK-ID, an approach to capture replication stress response factors. The chromatin reader TRIM24 was identified as a critical mediator of alternative lengthening of telomeres (ALTs) through a mechanism involving histone acetylation and SUMOylation signaling that, when disrupted, results in aberrant telomere function in ALT-positive cells.

TRIM24 directs replicative stress responses to maintain ALT telomeres via chromatin signaling

Condensin II activation by M18BP1 Borsellini, Conti, Cutts, Harris, et al. identify an interaction between M18BP1 and condensin II that is essential for condensin II activity and chromatin localization. MCPH1 keeps the interphase genome uncondensed by competing with M18BP1. A phosphorylation-driven switch allows M18BP1 to trigger condensation at mitotic onset.

Condensin II activation by M18BP1

Reconciling competing models on the roles of condensates and soluble complexes in transcription factor function Bremer et al. compare two competing models for how transcription factors mediate gene regulation: via phase separation or via soluble complex formation. They demonstrate that Gcn4 sequence variants can function as soluble complexes as well as heterotypic condensates but that condensates formed by variants with high affinities can dampen activities.

Reconciling competing models on the roles of condensates and soluble complexes in transcription factor function

Regulation of somatic hypermutation by higher-order chromatin structure Schoeberl et al. employ Tri-C to unravel the higher-order chromatin architecture underpinning the co-transcriptional mutagenesis of immunoglobulin genes during antibody maturation in human B cells. They provide evidence that antibody maturation occurs within a dynamic multiway hub wherein transcription and mutation of different genes occur non-competitively.

Regulation of somatic hypermutation by higher-order chromatin structure

Isoform-specific function of NSD3 in DNA replication stress confers resistance to PARP inhibitors in prostate cancer In this study, Zhu et al. demonstrate that upregulated NSD3S confers acquired PARPi resistance in prostate cancer cells. ATR drives the localization of NSD3S to stalled replication forks, where it protects nascent DNA from extensive degradation and ensures fork stabilization by antagonizing PTIP-dependent recruitment of the MRE11 nuclease.

Isoform-specific function of NSD3 in DNA replication stress confers resistance to PARP inhibitors in prostate cancer

Microprotein SMIM26 drives oxidative metabolism via serine-responsive mitochondrial translation Nah et al. identify the microprotein SMIM26 as a critical link between mitochondrial serine metabolism and complex I biogenesis. By scaffolding serine transporters and mitoribosomes, SMIM26 enables nutrient-responsive translation of mt-ND5, revealing a metabolite-gated mechanism for respiratory complex assembly with implications for development and cancer metabolism.

Microprotein SMIM26 drives oxidative metabolism via serine-responsive mitochondrial translation

The SWI/SNF-related protein SMARCA3 is a histone H3K23 ubiquitin ligase that regulates H3K9me3 in cancer Akano and Hebert et al. identify SMARCA3 as an E3 ligase for histone H3K23 ubiquitination, which stabilizes the repressive H3K9me3 mark. Frequently silenced in colorectal cancer, SMARCA3 regulates chromatin accessibility and the expression of cancer-associated genes, revealing a mechanistic link between histone ubiquitination and tumor suppression.

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FMRP drives mRNP targets into translationally silenced complexes Translational repression by FMRP has been attributed primarily to ribosome stalling. We show that FMRP sequesters its target mRNAs from translation initiation. FMRP binds not only to the transcript body but also directly to cap-bound eIF4E and poly(A)-tail-bound PABPC1. Through binding these two proteins, FMRP protects its target mRNAs from translation and decay.

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Mechanism of cotranslational protein N-myristoylation in human cells In structure-function studies, Gamerdinger and Echeverria et al. uncover the cotranslational mechanism of N-myristoyltransferases (NMTs), essential enzymes that attach a lipid anchor to newborn proteins. They show that NMT activity is orchestrated by a key regulator at the ribosomal tunnel exit, the nascent polypeptide-associated complex (NAC).

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CRAMP1’s surprising grip on linker histones In this issue of Molecular Cell, Ingham et al. and Matthews et al. report CRAMP1 as a key regulator of linker histone transcription in human cells.

CRAMP1’s surprising grip on linker histones

Metabolic compartmentalization via glycogenolysis-derived G1P bolsters T cell memory In this issue of Molecular Cell, Zhou et al. show that glycogenolysis-derived glucose-1-phosphate enhances glucose-6-phosphate dehydrogenase oligomerization and activity, promoting the formation of a liquid-liquid phase separation compartment containing glycogen. This channels glycogenolysis-derived glucose-6-phosphate into the pentose phosphate pathway, supporting CD8+ memory T cell fitness and antitumor effects.

Metabolic compartmentalization via glycogenolysis-derived G1P bolsters T cell memory