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Loss of Nuclear Envelope Integrity and Increased Oxidant Production Cause DNA Damage in Adult Hearts Deficient in PKP2: A Molecular Substrate of ARVC

Pérez-Hernández, Marta; van Opbergen, Chantal J M; Bagwan, Navratan; Rasmus Vissing, Christoffer; Marrón-Liñares, Grecia M; Zhang, Mingliang; Torres Vega, Estefania; Sorrentino, Andrea; Drici, Lylia; Sulek, Karolina; Zhai, Ruxu; Hansen, Finn B; Hørby Christensen, Alex; Boesgaard, Søren; Gustafsson, Finn; Rossing, Kasper; Small, Eric M; Davies, Michael J; Rothenberg, Eli; Sato, Priscila; Cerrone, Marina; Jensen, Thomas Hartvig Lindkær; Qvortrup, Klaus; Bundgaard, Henning; Delmar, Mario; Lundby, Alicia
BACKGROUND:gene, which encodes the PKP2 protein (plakophilin-2). METHODS:studied at a time of preserved left ventricular ejection fraction and in human induced pluripotent stem cell-derived PKP2-deficient myocytes. RESULTS: CONCLUSIONS:
PMID: 35959657
ISSN: 1524-4539
CID: 5287322

Therapy-induced senescence promotes breast cancer cells plasticity by inducing Lipocalin-2 expression

Morales-Valencia, Jorge; Lau, Lena; Martí-Nin, Teresa; Ozerdem, Ugur; David, Gregory
The acquisition of novel detrimental cellular properties following exposure to cytotoxic drugs leads to aggressive and metastatic tumors that often translates into an incurable disease. While the bulk of the primary tumor is eliminated upon exposure to chemotherapeutic treatment, residual cancer cells and non-transformed cells within the host can engage a stable cell cycle exit program named senescence. Senescent cells secrete a distinct set of pro-inflammatory factors, collectively termed the senescence-associated secretory phenotype (SASP). Upon exposure to the SASP, cancer cells undergo cellular plasticity resulting in increased proliferation, migration and epithelial-to-mesenchymal transition. The molecular mechanisms by which the SASP regulates these pro-tumorigenic features are poorly understood. Here, we report that breast cancer cells exposed to the SASP strongly upregulate Lipocalin-2 (LCN2). Furthermore, we demonstrate that LCN2 is critical for SASP-induced increased migration in breast cancer cells, and its inactivation potentiates the response to chemotherapeutic treatment in mouse models of breast cancer. Finally, we show that neoadjuvant chemotherapy treatment leads to LCN2 upregulation in residual human breast tumors, and correlates with worse overall survival. These findings provide the foundation for targeting LCN2 as an adjuvant therapeutic approach to prevent the emergence of aggressive tumors following chemotherapy.
PMID: 35953598
ISSN: 1476-5594
CID: 5287202

Shelterin is a dimeric complex with extensive structural heterogeneity

Zinder, John C; Olinares, Paul Dominic B; Svetlov, Vladimir; Bush, Martin W; Nudler, Evgeny; Chait, Brian T; Walz, Thomas; de Lange, Titia
Human shelterin is a six-subunit complex-composed of TRF1, TRF2, Rap1, TIN2, TPP1, and POT1-that binds telomeres, protects them from the DNA-damage response, and regulates the maintenance of telomeric DNA. Although high-resolution structures have been generated of the individual structured domains within shelterin, the architecture and stoichiometry of the full complex are currently unknown. Here, we report the purification of shelterin subcomplexes and reconstitution of the entire complex using full-length, recombinant subunits. By combining negative-stain electron microscopy (EM), cross-linking mass spectrometry (XLMS), AlphaFold modeling, mass photometry, and native mass spectrometry (MS), we obtain stoichiometries as well as domain-scale architectures of shelterin subcomplexes and determine that they feature extensive conformational heterogeneity. For POT1/TPP1 and POT1/TPP1/TIN2, we observe high variability in the positioning of the POT1 DNA-binding domain, the TPP1 oligonucleotide/oligosaccharide-binding (OB) fold, and the TIN2 TRFH domain with respect to the C-terminal domains of POT1. Truncation of unstructured linker regions in TIN2, TPP1, and POT1 did not reduce the conformational variability of the heterotrimer. Shelterin and TRF1-containing subcomplexes form fully dimeric stoichiometries, even in the absence of DNA substrates. Shelterin and its subcomplexes showed extensive conformational variability, regardless of the presence of DNA substrates. We conclude that shelterin adopts a multitude of conformations and argue that its unusual architectural variability is beneficial for its many functions at telomeres.
PMID: 35881804
ISSN: 1091-6490
CID: 5276382

Cryo-EM structure of the human CST-Polα/primase complex in a recruitment state

Cai, Sarah W; Zinder, John C; Svetlov, Vladimir; Bush, Martin W; Nudler, Evgeny; Walz, Thomas; de Lange, Titia
The CST-Polα/primase complex is essential for telomere maintenance and functions to counteract resection at double-strand breaks. We report a 4.6-Å resolution cryo-EM structure of human CST-Polα/primase, captured prior to catalysis in a recruitment state stabilized by chemical cross-linking. Our structure reveals an evolutionarily conserved interaction between the C-terminal domain of the catalytic POLA1 subunit and an N-terminal expansion in metazoan CTC1. Cross-linking mass spectrometry and negative-stain EM analysis provide insight into CST binding by the flexible POLA1 N-terminus. Finally, Coats plus syndrome disease mutations previously characterized to disrupt formation of the CST-Polα/primase complex map to protein-protein interfaces observed in the recruitment state. Together, our results shed light on the architecture and stoichiometry of the metazoan fill-in machinery.
PMID: 35578024
ISSN: 1545-9985
CID: 5284212

The very hungry bactericidal antibiotics

Rasouly, Aviram; Nudler, Evgeny
PMID: 35867771
ISSN: 1091-6490
CID: 5276052

Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer

Kurz, Emma; Hirsch, Carolina Alcantara; Dalton, Tanner; Shadaloey, Sorin Alberto; Khodadadi-Jamayran, Alireza; Miller, George; Pareek, Sumedha; Rajaei, Hajar; Mohindroo, Chirayu; Baydogan, Seyda; Ngo-Huang, An; Parker, Nathan; Katz, Matthew H G; Petzel, Maria; Vucic, Emily; McAllister, Florencia; Schadler, Keri; Winograd, Rafael; Bar-Sagi, Dafna
Aerobic exercise is associated with decreased cancer incidence and cancer-associated mortality. However, little is known about the effects of exercise on pancreatic ductal adenocarcinoma (PDA), a disease for which current therapeutic options are limited. Herein, we show that aerobic exercise reduces PDA tumor growth, by modulating systemic and intra-tumoral immunity. Mechanistically, exercise promotes immune mobilization and accumulation of tumor-infiltrating IL15Rα+ CD8 T cells, which are responsible for the tumor-protective effects. In clinical samples, an exercise-dependent increase of intra-tumoral CD8 T cells is also observed. Underscoring the translational potential of the interleukin (IL)-15/IL-15Rα axis, IL-15 super-agonist (NIZ985) treatment attenuates tumor growth, prolongs survival, and enhances sensitivity to chemotherapy. Finally, exercise or NIZ985 both sensitize pancreatic tumors to αPD-1, with improved anti-tumor and survival benefits. Collectively, our findings highlight the therapeutic potential of an exercise-oncology axis and identify IL-15 activation as a promising treatment strategy for this deadly disease.
PMID: 35660135
ISSN: 1878-3686
CID: 5231112

Ribodysgenesis: sudden genome instability in the yeast Saccharomyces cerevisiae arising from RNase H2 cleavage at genomic-embedded ribonucleotides

Sui, Yang; Epstein, Anastasiya; Dominska, Margaret; Zheng, Dao-Qiong; Petes, Thomas D; Klein, Hannah L
Ribonucleotides can be incorporated into DNA during replication by the replicative DNA polymerases. These aberrant DNA subunits are efficiently recognized and removed by Ribonucleotide Excision Repair, which is initiated by the heterotrimeric enzyme RNase H2. While RNase H2 is essential in higher eukaryotes, the yeast Saccharomyces cerevisiae can survive without RNase H2 enzyme, although the genome undergoes mutation, recombination and other genome instability events at an increased rate. Although RNase H2 can be considered as a protector of the genome from the deleterious events that can ensue from recognition and removal of embedded ribonucleotides, under conditions of high ribonucleotide incorporation and retention in the genome in a RNase H2-negative strain, sudden introduction of active RNase H2 causes massive DNA breaks and genome instability in a condition which we term 'ribodysgenesis'. The DNA breaks and genome instability arise solely from RNase H2 cleavage directed to the ribonucleotide-containing genome. Survivors of ribodysgenesis have massive loss of heterozygosity events stemming from recombinogenic lesions on the ribonucleotide-containing DNA, with increases of over 1000X from wild-type. DNA breaks are produced over one to two divisions and subsequently cells adapt to RNase H2 and ribonucleotides in the genome and grow with normal levels of genome instability.
PMID: 35748861
ISSN: 1362-4962
CID: 5282302

KATP channel trafficking

Yang, Hua-Qian; Echeverry, Fabio A; ElSheikh, Assmaa; Gando, Ivan; Anez Arredondo, Sophia; Samper, Natalie; Cardozo, Timothy; Delmar, Mario; Shyng, Show-Ling; Coetzee, William A
Sarcolemmal/plasmalemmal ATP-sensitive K+ (KATP) channels have key roles in many cell types and tissues. Hundreds of studies have described how the KATP channel activity and ATP sensitivity can be regulated by changes in the cellular metabolic state, by receptor signaling pathways and by pharmacological interventions. These alterations in channel activity directly translate to alterations in cell or tissue function, that can range from modulating secretory responses, such as insulin release from pancreatic β-cells or neurotransmitters from neurons, to modulating contractile behavior of smooth muscle or cardiac cells to elicit alterations in blood flow or cardiac contractility. It is increasingly becoming apparent, however, that KATP channels are regulated beyond changes in their activity. Recent studies have highlighted that KATP channel surface expression is a tightly regulated process with similar implications in health and disease. The surface expression of KATP channels is finely balanced by several trafficking steps including synthesis, assembly, anterograde trafficking, membrane anchoring, endocytosis, endocytic recycling and degradation. This review aims to summarize the physiological and pathophysiological implications of KATP channel trafficking and mechanisms that regulate KATP channel trafficking. A better understanding of this topic has potential to identify new approaches to develop therapeutically useful drugs to treat KATP channel-related diseases.
PMID: 35508187
ISSN: 1522-1563
CID: 5216232

Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia

Garcia-Bermudez, Javier; Badgley, Michael A; Prasad, Sheela; Baudrier, Lou; Liu, Yuyang; La, Konnor; Soula, Mariluz; Williams, Robert T; Yamaguchi, Norihiro; Hwang, Rosa F; Taylor, Laura J; de Stanchina, Elisa; Rostandy, Bety; Alwaseem, Hanan; Molina, Henrik; Bar-Sagi, Dafna; Birsoy, Kıvanç
Stress-adaptive mechanisms enable tumour cells to overcome metabolic constraints under nutrient and oxygen shortage. Aspartate is an endogenous metabolic limitation under hypoxic conditions, but the nature of the adaptive mechanisms that contribute to aspartate availability and hypoxic tumour growth are poorly understood. Here we identify GOT2-catalysed mitochondrial aspartate synthesis as an essential metabolic dependency for the proliferation of pancreatic tumour cells under hypoxic culture conditions. In contrast, GOT2-catalysed aspartate synthesis is dispensable for pancreatic tumour formation in vivo. The dependence of pancreatic tumour cells on aspartate synthesis is bypassed in part by a hypoxia-induced potentiation of extracellular protein scavenging via macropinocytosis. This effect is mutant KRAS dependent, and is mediated by hypoxia-inducible factor 1 (HIF1A) and its canonical target carbonic anhydrase-9 (CA9). Our findings reveal high plasticity of aspartate metabolism and define an adaptive regulatory role for macropinocytosis by which mutant KRAS tumours can overcome nutrient deprivation under hypoxic conditions.
PMID: 35726024
ISSN: 2522-5812
CID: 5278652

SHAPE-enabled fragment-based ligand discovery for RNA

Zeller, Meredith J; Favorov, Oleg; Li, Kelin; Nuthanakanti, Ashok; Hussein, Dina; Michaud, Auréliane; Lafontaine, Daniel A; Busan, Steven; Serganov, Alexander; Aubé, Jeffrey; Weeks, Kevin M
SignificanceRNA molecules encode proteins and play numerous regulatory roles in cells. Targeting RNA with small molecules, as is routine with proteins, would create broad opportunities for modulating biology and creating new drugs. However, this opportunity has been difficult to realize because creating novel small molecules that bind RNA, especially using modest resources, is challenging. This study integrates two widely used technologies, SHAPE chemical probing of RNA and fragment-based ligand discovery, to craft an innovative strategy for creating small molecules that bind to and modulate the activity of a structured RNA. The anticipated impact is high because the methods are simple, can be implemented in diverse research and discovery contexts, and lead to realistic druglike molecules.
PMID: 35561226
ISSN: 1091-6490
CID: 5214982