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Methyltransferase-like 3 (METTL3) and 14 (METTL14) are core subunits of the methyltransferase complex that catalyses messenger RNA N 6 -methyladenosine (m 6 A) modification. Despite the expanding list of m 6 A-dependent functions of the methyltransferase complex, the m 6 A-independent function of the METTL3 and METTL14 complex remains poorly understood. Here we show that genome-wide redistribution of METTL3 and METTL14 transcriptionally drives the senescence-associated secretory phenotype (SASP) in an m 6 A-independent manner. METTL14 is redistributed to the enhancers, whereas METTL3 is localized to the pre-existing NF-κB sites within the promoters of SASP genes during senescence. METTL3 and METTL14 are necessary for SASP. However, SASP is not regulated by m 6 A mRNA modification. METTL3 and METTL14 are required for both the tumour-promoting and immune-surveillance functions of senescent cells, which are mediated by SASP in vivo in mouse models. In summary, our results report an m 6 A-independent function of the METTL3 and METTL14 complex in transcriptionally promoting SASP during senescence. Here Liu et al. show that genome-wide redistribution of methyltransferase-like 3 and 14 transcriptionally promotes the senescence-associated secretory phenotype in an m 6 A-independent manner.

Cyclic cGMP-AMP synthase (cGAS) is a pattern recognition cytosolic DNA sensor that is essential for cellular senescence. cGAS promotes inflammatory senescence-associated secretory phenotype (SASP) through recognizing cytoplasmic chromatin during senescence. cGAS-mediated inflammation is essential for the antitumor effects of immune checkpoint blockade. However, the mechanism by which cGAS recognizes cytoplasmic chromatin is unknown. Here we show that topoisomerase 1-DNA covalent cleavage complex (TOP1cc) is both necessary and sufficient for cGAS-mediated cytoplasmic chromatin recognition and SASP during senescence. TOP1cc localizes to cytoplasmic chromatin and TOP1 interacts with cGAS to enhance the binding of cGAS to DNA. Retention of TOP1cc to cytoplasmic chromatin depends on its stabilization by the chromatin architecture protein HMGB2. Functionally, the HMGB2-TOP1cc-cGAS axis determines the response of orthotopically transplanted ex vivo therapy-induced senescent cells to immune checkpoint blockade in vivo. Together, these findings establish a HMGB2-TOP1cc-cGAS axis that enables cytoplasmic chromatin recognition and response to immune checkpoint blockade. Here, the authors show that the topoisomerase 1-DNA covalent cleavage complex plays a critical role in mediating cytoplasmic chromatin fragments recognition by cyclic GMP-AMP synthase during senescence. The proposed axis is crucial to promote the inflammatory senescence-associated secretory phenotype and to enable the response to immune checkpoint blockade.

CARM1 is often overexpressed in human cancers including in ovarian cancer. However, therapeutic approaches based on CARM1 expression remain to be an unmet need. Cancer cells exploit adaptive responses such as the endoplasmic reticulum (ER) stress response for their survival through activating pathways such as the IRE1α/XBP1s pathway. Here, we report that CARM1-expressing ovarian cancer cells are selectively sensitive to inhibition of the IRE1α/XBP1s pathway. CARM1 regulates XBP1s target gene expression and directly interacts with XBP1s during ER stress response. Inhibition of the IRE1α/XBP1s pathway was effective against ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model. Our data show that pharmacological inhibition of the IRE1α/XBP1s pathway alone or in combination with immune checkpoint blockade represents a therapeutic strategy for CARM1-expressing cancers. The unfolded protein response (UPR) promotes cell survival in cancers with hyperactive ER stress response. Here the authors show that CARM1, an arginine methyltransferase, controls the IRE1α/XBP1 pathway of the UPR and the inhibition of this pathway can inhibit growth in CARM1 expressing ovarian cancers.

ARID1A inactivation causes mitotic defects. Paradoxically, cancers with high ARID1A mutation rates typically lack copy number alterations (CNAs). Here, we show that ARID1A inactivation causes defects in telomere cohesion, which selectively eliminates gross chromosome aberrations during mitosis. ARID1A promotes the expression of cohesin subunit STAG1 that is specifically required for telomere cohesion. ARID1A inactivation causes telomere damage that can be rescued by STAG1 expression. Colony formation capability of single cells in G 2 /M, but not G 1 phase, is significantly reduced by ARID1A inactivation. This correlates with an increase in apoptosis and a reduction in tumor growth. Compared with ARID1A wild-type tumors, ARID1A -mutated tumors display significantly less CNAs across multiple cancer types. Together, these results show that ARID1A inactivation is selective against gross chromosome aberrations through causing defects in telomere cohesion, which reconciles the long-standing paradox between the role of ARID1A in maintaining mitotic integrity and the lack of genomic instability in ARID1A -mutated cancers. Cells with ARID1A mutations exhibit mitotic defects, yet show surprisingly low levels of copy number defects. Here, Zhao et al. resolve this issue by showing that ARID1A loss causes defects in telomere cohesion, which selects against gross alterations in copy number.

Background Linker histones constitute a class of proteins that are responsible for the formation of higher-order chromatin structures. Core histones are integral components of nucleosome core particles (NCPs), whereas linker histones bind to linker DNA between NCPs. Heterochromatin protein 1 binding protein 3 (HP1BP3) displays sequence similarity to linker histones, with the exception of the presence of three globular domains in its central region. However, the function of HP1BP3 as a linker histone has not been analyzed previously. The present study aimed to elucidate the function of full-length HP1BP3 as a linker histone variant. Results The results of biochemical analyses demonstrate that HP1BP3 efficiently binds to NCPs with similar efficiency as linker histones, thereby forming a chromatosome. Notwithstanding the presence of three globular domains, the results suggest that a single HP1BP3 binds to a single NCP under our biochemical assay condition. Moreover, our findings revealed that the NCP binding activity of HP1BP3 is regulated by linker histone chaperones, nucleophosmin (NPM1) and template activating factor-I (TAF-I). The globular domains and the C-terminal disordered region of HP1BP3 are responsible for binding to histone chaperones. Chromatin immunoprecipitation-sequence analyses demonstrated that HP1BP3 exhibited weak preferences for the genomic loci where histone H3 active modification marks were enriched, whereas a linker histone variant, H1.2, showed weak preferences for the genomic loci where histone H3 inactive modification marks were enriched. It is noteworthy that the preferential binding tendencies of HP1BP3 and H1.2 to active and inactive genomic loci, respectively, are diminished upon the knockdown of either NPM1 or TAF-I. Conclusions Our findings indicate that HP1BP3 functions as a linker histone variant and that the chromatin binding preference of linker histones, including HP1BP3, is regulated by linker histone chaperones.

Alterations in components of the SWI/SNF chromatin-remodeling complex occur in ~20% of all human cancers. For example, is mutated in up to 62% of clear cell ovarian carcinoma (OCCC), a disease currently lacking effective therapies. Here we show that mutation creates a dependence on glutamine metabolism. SWI/SNF represses ( ) and ARID1A inactivation upregulates GLS1. ARID1A inactivation increases glutamine utilization and metabolism through the tricarboxylic acid cycle to support aspartate synthesis. Indeed, glutaminase inhibitor CB-839 suppresses the growth of mutant, but not wildtype, OCCCs in both orthotopic and patient-derived xenografts. In addition, glutaminase inhibitor CB-839 synergizes with immune checkpoint blockade anti-PDL1 antibody in a genetic OCCC mouse model driven by conditional inactivation. Our data indicate that pharmacological inhibition of glutaminase alone or in combination with immune checkpoint blockade represents an effective therapeutic strategy for cancers involving alterations in the SWI/SNF complex such as mutations.

Chemoresistance is one of the leading causes of mortality in breast cancer (BC). Understanding the molecules regulating chemoresistance is critical in order to combat chemoresistant BC. Drug efflux pump ABCB1 is overexpressed in chemoresistant neoplasms where it effluxes various chemotherapeutic agents from cells. Because it is expressed in normal and cancerous cells alike, attempts at targeting ABCB1 directly have failed due to low specificity and disruption of normal tissue. A proposed method to inhibit ABCB1 is to target its cancer-specific, upstream regulators, mitigating damage to normal tissue. Few such cancer-specific upstream regulators have been described. Here we characterize ROR1 as an upstream regulator of ABCB1. ROR1 is highly expressed during development but not expressed in normal adult tissue. It is however highly expressed in several cancers. ROR1 is overexpressed in chemoresistant BC where it correlates with poor therapy response and tumor recurrence. Our data suggests, ROR1 inhibition sensitizes BC cells to chemo drugs. We also show ROR1 regulates ABCB1 stability and transcription via MAPK/ERK and p53. Validating our overall findings, inhibition of ROR1 directly correlated with decreased efflux of chemo-drugs from cells. Overall, our results highlight ROR1’s potential as a therapeutic target for multidrug resistant malignancies.

Lipomas, benign adipose tissue tumors, are a common occurrence but currently, the options for their treatment are limited, with surgical excision being the most frequently used management pathway. This scenario can often lead to unsatisfactory cosmetic results and significant patient discomfort. This paper introduces a novel technique, percutaneous microwave ablation with liposuction, to address these challenges. The innovative procedure aims to enhance patient satisfaction, minimize post-operative discomfort, and improve aesthetic outcomes. The technique involves two key steps: (1) the application of percutaneous microwave ablation to selectively disrupt the lipoma cells, followed by (2) a targeted liposuction procedure to remove the ablated lipoma tissue. Our approach optimizes the removal of the lipoma and preserves the surrounding healthy tissue, reducing the risk of local recurrence and improving the cosmetic result. The use of preoperative ultrasound imaging allows for precise localization and delineation of the lipoma, aiding in the planning and execution of the procedure. This novel approach to lipoma treatment is reliable, associated with minimal morbidity, and consistently yields effective results. Additionally, it provides a new perspective on lipoma management, potentially changing the paradigm of current treatment approaches. Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Methyltransferase-like 3 (METTL3) and 14 (METTL14) are core subunits of the methyltransferase complex that catalyses messenger RNA N.sup.6-methyladenosine (m.sup.6A) modification. Despite the expanding list of m.sup.6A-dependent functions of the methyltransferase complex, the m.sup.6A-independent function of the METTL3 and METTL14 complex remains poorly understood. Here we show that genome-wide redistribution of METTL3 and METTL14 transcriptionally drives the senescence-associated secretory phenotype (SASP) in an m.sup.6A-independent manner. METTL14 is redistributed to the enhancers, whereas METTL3 is localized to the pre-existing NF-[kappa]B sites within the promoters of SASP genes during senescence. METTL3 and METTL14 are necessary for SASP. However, SASP is not regulated by m.sup.6A mRNA modification. METTL3 and METTL14 are required for both the tumour-promoting and immune-surveillance functions of senescent cells, which are mediated by SASP in vivo in mouse models. In summary, our results report an m.sup.6A-independent function of the METTL3 and METTL14 complex in transcriptionally promoting SASP during senescence.