Structural Maintenance Of Chromosomes Research Articles

A Novel Regulatory Motif at the Hinge Dimer Interface of the MksB Mediates Dimerization and DNA Binding Activity.

The Structural Maintenance of Chromosome (SMC) protein is essential for various cellular processes, including chromosome organization, DNA repair, and genome stability. MksB, an alternative SMC protein present in prokaryotes, comprises a hinge dimerization domain and an ABC ATPase head domain linked by a coiled-coil arm. While hinge dimerization in bacterial and eukaryotic SMCs is attributed to conserved glycines, our study unveils the critical role of a novel KDDR motif located at a loop near the hinge dimer interface in Mycobacterium smegmatis MksB (MsMksB). We demonstrate the regulatory role of this motif in MsMksB dimerization and DNA binding activity. The K600D mutation in the KDDR motif induces MsMksB dimer-to-monomer conversion, highlighting the significance of this motif in MsMksB dimerization. Mass spectrometry-based mapping of the DNA binding site revealed the lysine's involvement in protein-DNA interaction. Monomers of the hinge domain lose DNA binding activity, and MsMksB single-arm mutants exhibit reduced DNA binding and ATPase activity, underscoring the importance of hinge-mediated dimerization in MsMksB function. Notably, the R603D mutant retains dimerization but shows compromised ATPase and DNA binding activities. Mutants with defective ATPase activity exhibit impaired DNA condensation in vivo. These findings provide novel regulatory insight into the mechanism of MksB dimerization and DNA binding, uncovering the fundamental processes of chromosome condensation and segregation.

Deciphering Plasmodium Condensin Core Subunits of Structural Maintenance of Chromosomes 2 (SMC2) as a Putative Drug Target for Antimalarial Drug

Background: The structural maintenance of chromosomes (SMC) proteins plays a noteworthy role in chromosome dynamics. Several recent studies reported that the condensin core subunits of structural maintenance of chromosomes 2 (SMC2) play important roles in the atypical mitosis of the Plasmodium life cycle and may perform different functions during different proliferative stages. For eukaryotes, the structural maintenance of chromosomes (SMC) proteins are divided into six subunits and form three heterodimers of structural maintenance of chromosomes (SMC1/3) cohesion complex, structural maintenance of chromosomes (SMC2/4) condensin complex, and structural maintenance of chromosomes (SMC5/6) complex for chromosome cohesion, condensation, and DNA damage repair, respectively. Objective: The objective of this study was to investigate the structural maintenance of chromosomes 2 (SMC2) protein of P. falciparum as a putative drug target of malariacausing Plasmodium falciparum. Methods: In this study, we investigated the structural maintenance of chromosomes 2 (SMC2) protein of P. falciparum as a putative drug target of malaria-causing P. falciparum by using in-silico approaches like Homology modeling, in-silico evaluation of the modeled structure, molecular docking study to investigate the interaction of receptor-ligand, and molecular dynamic simulation study with MM calculation. Results: We reported the structural maintenance of chromosomes 2 (SMC2) protein of P. falciparum as a potent drug target that can pave the way for novel drug discovery to mitigate malaria. Conclusion: In-silico-based studies play a significant role in understanding any protein for potential drug development.

Symmetry of loop extrusion by dimeric SMC complexes is DNA-tension-dependent.

Structural maintenance of chromosome (SMC) complexes organize and regulate genomes via DNA loop extrusion. During this process, the complexes increase the loop size by reeling in DNA from one or both sides of the loop. The factors governing this symmetry remain unclear. Here, we combine single-molecule analysis and molecular dynamic simulations to investigate the symmetry of loop extrusion of various SMC complexes. We find that whereas monomeric condensin and cohesin are one-sided extruders, the symmetry of dimeric SMCs, such as Smc5/6 and Wadjet, is DNA tension dependent. At low DNA tension (< 0.1pN), Smc5/6 and Wadjet extrude DNA from both sides of the loop. At higher tension, however, they transition to a behavior akin to one-sided extruders, yet still capable of extruding from one or the other side thereby switching the direction of extrusion. Our simulations further reveal that thermal fluctuations significantly influence loop extrusion symmetry, causing variations in DNA reeling rates between the two motors in the dimeric complexes and their direction switching at stalling tensions. Our findings challenge the previous view of loop extrusion symmetry as a fixed characteristic, revealing its dynamic nature and regulation by both intrinsic protein properties and extrinsic factors.

Positive Selection Drives the Evolution of the Structural Maintenance of Chromosomes (SMC) Complexes.

Structural Maintenance of Chromosomes (SMC) complexes are an evolutionary conserved protein family. In most eukaryotes, three SMC complexes have been characterized, as follows: cohesin, condensin, and SMC5/6 complexes. These complexes are involved in a plethora of functions, and defects in SMC genes can lead to an increased risk of chromosomal abnormalities, infertility, and cancer. To investigate the evolution of SMC complex genes in mammals, we analyzed their selective patterns in an extended phylogeny. Signals of positive selection were identified for condensin NCAPG, for two SMC5/6 complex genes (SMC5 and NSMCE4A), and for all cohesin genes with almost exclusive meiotic expression (RAD21L1, REC8, SMC1B, and STAG3). For the latter, evolutionary rates correlate with expression during female meiosis, and most positively selected sites fall in intrinsically disordered regions (IDRs). Our results support growing evidence that IDRs are fast evolving, and that they most likely contribute to adaptation through modulation of phase separation. We suggest that the natural selection signals identified in SMC complexes may be the result of different selective pressures: a host-pathogen arms race in the condensin and SMC5/6 complexes, and an intragenomic conflict for meiotic cohesin genes that is similar to that described for centromeres and telomeres.

The physical chemistry of interphase loop extrusion.

Loop extrusion constitutes a universal mechanism of genome organization, whereby structural maintenance of chromosomes (SMC) protein complexes load onto the chromatin fiber and generate DNA loops of increasingly-larger sizes until their eventual release. In mammalian interphase cells, loop extrusion is mediated by the cohesin complex, which is dynamically regulated by the interchange of multiple accessory proteins. Although these regulators bind the core cohesin complex only transiently, their disruption can dramatically alter cohesin dynamics, gene expression, chromosome morphology and contact patterns. Still, a theory of how cohesin regulators and their molecular interplay with the core complex modulate genome folding remains at large. Here we derive a model of cohesin loop extrusion from first principles, based on in vivo measurements of the abundance and dynamics of cohesin regulators. We systematically evaluate potential chemical reaction networks that describe the association of cohesin with its regulators and with the chromatin fiber. Remarkably, experimental observations are consistent with only a single biochemical reaction cycle, which results in a unique minimal model that may be fully parameterized by quantitative protein measurements. We demonstrate how distinct roles for cohesin regulators emerge simply from the structure of the reaction network, and how their dynamic exchange can regulate loop extrusion kinetics over time-scales that far exceed their own chromatin residence times. By embedding our cohesin biochemical reaction network within biophysical chromatin simulations, we evidence how variations in regulatory protein abundance can alter chromatin architecture across multiple length- and time-scales. Predictions from our model are corroborated by biophysical and biochemical assays, optical microscopy observations, and Hi-C conformation capture techniques. More broadly, our theoretical and numerical framework bridges the gap between in vitro observations of extrusion motor dynamics at the molecular scale and their structural consequences at the genome-wide level.

BRCA1/BRC-1 and SMC-5/6 regulate DNA repair pathway engagement during Caenorhabditis elegans meiosis.

The preservation of genome integrity during sperm and egg development is vital for reproductive success. During meiosis, the tumor suppressor BRCA1/BRC-1 and structural maintenance of chromosomes 5/6 (SMC-5/6) complex genetically interact to promote high fidelity DNA double strand break (DSB) repair, but the specific DSB repair outcomes these proteins regulate remain unknown. Using genetic and cytological methods to monitor resolution of DSBs with different repair partners in Caenorhabditis elegans, we demonstrate that both BRC-1 and SMC-5 repress intersister crossover recombination events. Sequencing analysis of conversion tracts from homolog-independent DSB repair events further indicates that BRC-1 regulates intersister/intrachromatid noncrossover conversion tract length. Moreover, we find that BRC-1 specifically inhibits error prone repair of DSBs induced at mid-pachytene. Finally, we reveal functional interactions of BRC-1 and SMC-5/6 in regulating repair pathway engagement: BRC-1 is required for localization of recombinase proteins to DSBs in smc-5 mutants and enhances DSB repair defects in smc-5 mutants by repressing theta-mediated end joining (TMEJ). These results are consistent with a model in which some functions of BRC-1 act upstream of SMC-5/6 to promote recombination and inhibit error-prone DSB repair, while SMC-5/6 acts downstream of BRC-1 to regulate the formation or resolution of recombination intermediates. Taken together, our study illuminates the coordinated interplay of BRC-1 and SMC-5/6 to regulate DSB repair outcomes in the germline.

Amplified Cell Cycle Genes Identified in High-Grade Serous Ovarian Cancer.

The objective of this study was to identify differentially expressed genes and their potential influence on the carcinogenesis of serous-type ovarian cancer tumors. Serous cancer is an epithelial ovarian cancer subtype and is the most common type of ovarian cancer. Transcriptomic profiles of serous cancer and non-cancerous datasets were obtained from the Gene Expression Omnibus (GEO-NCBI). Differentially expressed genes were then derived from those profiles; the identified genes were consistently upregulated in three or more transcriptomic profiles. These genes were considered as the serous ovarian cancer gene set for further study. The serous gene set derived from the transcriptomic profiles was then evaluated for ontological functional analysis using the Molecular Signatures Database. Next, we examined the mutational impact of this serous gene set on the transcriptomic profile of high-grade serous ovarian (HGSO) adenocarcinoma using the cBioPortal database. Results from OncoPrint revealed that 26 genes were amplified in more than 5% of HGSO cancer patients. Interestingly, several of these genes are involved in cell cycle processes, including genes ATPase family AAA domain containing 2 (ATAD2), recQ-like helicase 4 (RECQL4), cyclin E1 (CCNE1), anti-silencing function 1B histone chaperone (ASF1B), ribonuclease H2 subunit A (RNASEH2A), structural maintenance of chromosome 4 (SMC4), cell division cycle associated 20 (CDC20), and cell division cycle associated 8 (CDCA8). The receiver operating characteristic (ROC) curve results also revealed higher specificity and sensitivity for this subtype of tumors. Furthermore, these genes may affect the recurrence of serous ovarian carcinogenesis. Overall, our analytical study identifies cell cycle-related genes that can potentially be targeted as diagnostic and prognostic markers for serous ovarian cancer.

Condensin I folds the Caenorhabditis elegans genome.

The structural maintenance of chromosome (SMC) complexes-cohesin and condensins-are crucial for chromosome separation and compaction during cell division. During the interphase, mammalian cohesins additionally fold the genome into loops and domains. Here we show that, in Caenorhabditis elegans, a species with holocentric chromosomes, condensin I is the primary, long-range loop extruder. The loss of condensin I and its X-specific variant, condensin IDC, leads to genome-wide decompaction, chromosome mixing and disappearance of X-specific topologically associating domains, while reinforcing fine-scale epigenomic compartments. In addition, condensin I/IDC inactivation led to the upregulation of X-linked genes and unveiled nuclear bodies grouping together binding sites for the X-targeting loading complex of condensin IDC. C. elegans condensin I/IDC thus uniquely organizes holocentric interphase chromosomes, akin to cohesin in mammals, as well as regulates X-chromosome gene expression.

Cryo-EM structures of Smc5/6 in multiple states reveal its assembly and functional mechanisms.

Smc5/6 is a member of the eukaryotic structural maintenance of chromosomes (SMC) family of complexes with important roles in genome maintenance and viral restriction. However, limited structural understanding of Smc5/6 hinders the elucidation of its diverse functions. Here, we report cryo-EM structures of the budding yeast Smc5/6 complex in eight-subunit, six-subunit and five-subunit states. Structural maps throughout the entire length of these complexes reveal modularity and key elements in complex assembly. We show that the non-SMC element (Nse)2 subunit supports the overall shape of the complex and uses a wedge motif to aid the stability and function of the complex. The Nse6 subunit features a flexible hook region for attachment to the Smc5 and Smc6 arm regions, contributing to the DNA repair roles of the complex. Our results also suggest a structural basis for the opposite effects of the Nse1-3-4 and Nse5-6 subcomplexes in regulating Smc5/6 ATPase activity. Collectively, our integrated structural and functional data provide a framework for understanding Smc5/6 assembly and function.

NSE5 subunit interacts with distant regions of the SMC arms in the Physcomitrium patens SMC5/6 complex.

Structural maintenance of chromosome (SMC) complexes play roles in cohesion, condensation, replication, transcription, and DNA repair. Their cores are composed of SMC proteins with a unique structure consisting of an ATPase head, long arm, and hinge. SMC complexes form long rod-like structures, which can change to ring-like and elbow-bent conformations upon binding ATP, DNA, and other regulatory factors. These SMC dynamic conformational changes are involved in their loading, translocation, and DNA loop extrusion. Here, we examined the binding and role of the PpNSE5 regulatory factor of Physcomitrium patens PpSMC5/6 complex. We found that the PpNSE5 C-terminal half (aa230-505) is required for binding to its PpNSE6 partner, while the N-terminal half (aa1-230) binds PpSMC subunits. Specifically, the first 71 amino acids of PpNSE5 were required for binding to PpSMC6. Interestingly, the PpNSE5 binding required the PpSMC6 head-proximal joint region and PpSMC5 hinge-proximal arm, suggesting a long distance between binding sites on PpSMC5 and PpSMC6 arms. Therefore, we hypothesize that PpNSE5 either links two antiparallel SMC5/6 complexes or binds one SMC5/6 in elbow-bent conformation, the later model being consistent with the role of NSE5/NSE6 dimer as SMC5/6 loading factor to DNA lesions. In addition, we generated the P.patens Ppnse5KO1 mutant line with an N-terminally truncated version of PpNSE5, which exhibited DNA repair defects while keeping a normal number of rDNA repeats. As the first 71 amino acids of PpNSE5 are required for PpSMC6 binding, our results suggest the role of PpNSE5-PpSMC6 interaction in SMC5/6 loading to DNA lesions.

Structural maintenance of chromosomes and associated genetic disorders

Structural maintenance of chromosomes (SMC), including cohesin, condensin and the SMC5/6 complex, are protein complexes which maintain the higher structure and dynamic stability of chromatin. Such circular complexes, with similar structures, play pivotal roles in chromatid cohesion, chromosomal condensation, DNA replication and repair, as well as gene transcription. Despite extensive research on the functions of the SMCs, our understanding of the SMC5/6 complex has remained limited compared with the other two complexes. This article has reviewed the architecture and crucial physiological roles of the SMCs, and explored the associated phenotypes resulting from mutations of the SMC components such as Cornelia de Lange syndrome (CdLS) and microcephaly, with an aim to provide insights into their functions in eukaryotic cells and implications for human diseases.

Identification of SMC2 and SMC4 as prognostic markers in breast cancer through bioinformatics analysis.

Breast cancer (BRCA) is one of the most common malignant tumors. The structural maintenance of chromosome (SMC) gene family has been shown to play an important role in human cancers. However, the role of SMC families in BRCA is unclear. This study aimed to explore the role and potential clinical value of whole SMCs in BRCA. TIMER and UALCAN database were used to analysis the expression level. Genetic variations were analyzed by cBioPortal. Promoter methylation and protein level were analyzed by UCLCAN. GO and KEGG were analyzed by Metascape database. Prognostic value of SMCs was analyzed by Kaplan-Meier and multivariate cox regression analyses. Immune infiltration analysis was conducted by CIBERSORT. Immunotherapy outcome prediction was conducted by Cancer Immunome Atlas. Targeted drug therapy outcome prediction was taken by GDSC and R language. The cell viability was tested by CCK8 and migration was tested by wound healing assay. Xenograft model was used to investigate the in vivo role of SMC2. Expression levels of SMC1A, SMC2, SMC4, SMC5 and SMC6 mRNA were increased in BRCA tissues, and negatively correlated with promoter methylation. Overexpression of SMC2 and SMC4 was negatively correlated with survival. Function of SMCs family regulatory genes was mainly related to ATPase activity. Expression of most SMCs was negatively correlated with immunotherapy and drug therapy outcomes. Interfere SMC2 and SMC4 decreased IC50 values of 5-fluorouracil and oxaliplatin and inhibited the migration of MCF7 cells. Tumor growth and weights were significantly decreased in si-SMC2 groups. Combined bioinformatics and clinical specimen analysis verified SMC2 and SMC4 as independent prognostic factors in BRCA, suggesting their significance for the diagnosis and treatment of BRCA.

SMC2 knockdown inhibits malignant progression of lung adenocarcinoma by upregulating BTG2 expression

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer worldwide. Structural maintenance of chromosomes 2 (SMC2) serves as a predictor of poor prognosis across various cancer types. This study aims to explore the role and underlying mechanisms of SMC2 in LUAD progression. The expression of SMC2 in LUAD tissues and its correlation with prognosis were analyzed by public databases. Knockdown of SMC2 was performed to assess the proliferation, migration and invasion ability of LUAD cells. Bulk RNA sequencing analysis identified enriched cellular pathways and remarkable upregulation of BTG anti-proliferation factor 2 (BTG2) expression after SMC2 knockdown in LUAD cells. Then, BTG2 was silenced to assess the malignant behavior of LUAD cells. Subcutaneous transplantation and intracranial tumor models of LUAD cells in BALB/c nude mice were established to assess the antineoplastic effect of SMC2 knockdown in vivo. Additionally, a lung metastasis model was created to evaluate the pro-metastatic effect of SMC2. Our findings indicated that SMC2 was upregulated in LUAD tissues and cell lines, with higher expression correlating with poor prognosis. SMC2 silencing suppressed the proliferation, migration and invasion ability of LUAD cells by upregulating BTG2 expression via p53 and inactivating ERK and AKT pathways. BTG2 silencing reversed the effects of SMC2 downregulation on malignant behaviors of LUAD cells and restored the phosphorylated ERK and AKT levels. Furthermore, SMC2 knockdown effectively prevented the formation of subcutaneous, intracranial and metastatic tumor in vivo, and upregulation of BTG2 expression after SMC2 knockdown was confirmed in tumor models. This study revealed that SMC2 knockdown restrained the malignant progression of LUAD through upregulation of BTG2 expression and inactivation of ERK and AKT pathways, and SMC2 could be a potential therapeutic target for LUAD treatment.

Members of the paralogous gene family 12 from the Lyme disease agent Borrelia burgdorferi are non-specific DNA-binding proteins.

Lyme disease is the most prevalent vector-borne infectious disease in Europe and the USA. Borrelia burgdorferi, as the causative agent of Lyme disease, is transmitted to the mammalian host during the tick blood meal. To adapt to the different encountered environments, Borrelia has adjusted the expression pattern of various, mostly outer surface proteins. The function of most B. burgdorferi outer surface proteins remains unknown. We determined the crystal structure of a previously uncharacterized B. burgdorferi outer surface protein BBK01, known to belong to the paralogous gene family 12 (PFam12) as one of its five members. PFam12 members are shown to be upregulated as the tick starts its blood meal. Structural analysis of BBK01 revealed similarity to the coiled coil domain of structural maintenance of chromosomes (SMC) protein family members, while functional studies indicated that all PFam12 members are non-specific DNA-binding proteins. The residues involved in DNA binding were identified and probed by site-directed mutagenesis. The combination of SMC-like proteins being attached to the outer membrane and exposed to the environment or located in the periplasm, as observed in the case of PFam12 members, and displaying the ability to bind DNA, represents a unique feature previously not observed in bacteria.

NCAPH serves as a prognostic factor and promotes the tumor progression in glioma through PI3K/AKT signaling pathway.

Non-SMC (Structural Maintenance of Chromosomes) condensin I complex subunit H (NCAPH) has been shown to facilitate progression and predict adverse prognostic outcome in many cancer types. However, the function of NCAPH in gliomas is still unclear. Series of experiments were taken to uncover the function of NCAPH in glioma. The expression of NCAPH and potential mechanism regulating progression of glioma was verified by bioinformatics analysis. Lentiviral transfection was used for establishment of loss-of-function and gain-of-function cell lines. CCK-8 assay and Colony-formation assay were used to evaluate proliferation. Transwell assay and Cell wound healing assay were used to assess migration and invasion. Cell cycle and apoptosis were measured by flow cytometry. Protein and RNA were quantified by WB and RT-PCR, respectively. The nude mice model of glioma was used to evaluate the effect of NCAPH in vivo. The expression of NCAPH increased significantly in glioma tissues and correlated with WHO grade, IDH wild-type and non-1p/19q codeletion. Glioma patients with high expression of NCAPH had an undesirable prognosis. Functionally, upregulated NCAPH promotes the malignant hallmarks of glioma cells in vivo and in vitro. NCAPH correlated with DNA damage repair ability of glioma cells and facilitated the proliferation, invasion, and migration of glioma cells by promoting the PI3K/AKT signaling pathway. This study identifies the important pro-tumor role of NCAPH in glioma and suggests that NCAPH is a potential therapeutic target.

Transient crosslinking controls the condensate formation pathway within chromatin networks.

The network structure of densely packed chromatin within the nucleus of eukaryotic cells acts in concert with nonequilibrium processes. Using statistical physics simulations, we explore the control provided by transient crosslinking of the chromatin network by structural-maintenance-of-chromosome (SMC) proteins over (i) the physical properties of the chromatin network and (ii) condensate formation of embedded molecular species. We find that the density and lifetime of transient SMC crosslinks regulate structural relaxation modes and tune the sol-vs-gel state of the chromatin network, which imparts control over the kinetic pathway to condensate formation. Specifically, lower density, shorter-lived crosslinks induce sollike networks and a droplet-fusion pathway, whereas higher density, longer-lived crosslinks induce gellike networks and an Ostwald-ripening pathway.

Proteomic profiling of Arabidopsis G-protein β subunit AGB1 mutant under salt stress.

Salt stress is a limiting environmental factor that inhibits plant growth in most ecological environments. The functioning of G-proteins and activated downstream signaling during salt stress is well established and different G-protein subunits and a few downstream effectors have been identified. Arabidopsis G-protein β-subunit (AGB1) regulates the movement of Na+ from roots to shoots along with a significant role in controlling Na+ fluxes in roots, however, the molecular mechanism of AGB1 mediated salt stress regulation is not well understood. Here, we report the comparative proteome profiles of Arabidopsis AGB1 null mutant agb1-2 to investigate how the absence of AGB1 modulates the protein repertoire in response to salt stress. High-resolution two-dimensional gel electrophoresis (2-DE) showed 27 protein spots that were differentially modulated between the control and NaCl treated agb1-2 seedlings of which seven were identified by mass spectrometry. Functional annotation and interactome analysis indicated that the salt-responsive proteins were majorly associated with cellulose synthesis, structural maintenance of chromosomes, DNA replication/repair, organellar RNA editingand indole glucosinolate biosynthesis. Further exploration of the functioning of these proteins could serve as a potential stepping stone for dissection of molecular mechanism of AGB1 functions during salt stress and in long run could be extrapolated to crop plants for salinity stress management.

Yin Yang 1 regulates cohesin complex protein SMC3 in mouse hematopoietic stem cells

AbstractYin Yang 1 (YY1) and structural maintenance of chromosomes 3 (SMC3) are 2 critical chromatin structural factors that mediate long-distance enhancer-promoter interactions and promote developmentally regulated changes in chromatin architecture in hematopoietic stem/progenitor cells (HSPCs). Although YY1 has critical functions in promoting hematopoietic stem cell (HSC) self-renewal and maintaining HSC quiescence, SMC3 is required for proper myeloid lineage differentiation. However, many questions remain unanswered regarding how YY1 and SMC3 interact with each other and affect hematopoiesis. We found that YY1 physically interacts with SMC3 and cooccupies with SMC3 at a large cohort of promoters genome wide, and YY1 deficiency deregulates the genetic network governing cell metabolism. YY1 occupies the Smc3 promoter and represses SMC3 expression in HSPCs. Although deletion of 1 Smc3 allele partially restores HSC numbers and quiescence in YY1 knockout mice, Yy1−/−Smc3+/− HSCs fail to reconstitute blood after bone marrow transplant. YY1 regulates HSC metabolic pathways and maintains proper intracellular reactive oxygen species levels in HSCs, and this regulation is independent of the YY1–SMC3 axis. Our results establish a distinct YY1–SMC3 axis and its impact on HSC quiescence and metabolism.

Abstract 5426: SMC2 orchestrates non-small cell lung cancer proliferation, invasion, and metastasis by modulating the ERK/AKT/NF-κB pathways

Abstract Chromatin instability has been associated with the expression of structural maintenance of chromosomes (SMC) family members and is a common feature in many tumors. SMC family members have been associated with poor outcomes in several cancer types. However, little is known about their functions and mechanisms in promoting cancer progression, particularly in non-small cell lung cancer (NSCLC). Here, we evaluated the expression of SMC family members in the tumor microenvironment of NSCLC specimens using single-cell RNA sequencing analyses. After a survival analysis, it was found that the sole factor associated with a poor prognosis for NSCLC was member SMC2 expression. Immunohistochemistry was used with data from the Human Protein Atlas, the Cancer Genome Atlas, and the Gene Expression Omnibus databases to confirm the overexpression of SMC2 in NSCLC. We demonstrated that SMC2 regulates not only the fluctuations in the critical states of tumor cells, which are defined by different transcriptome and metabolic properties but also coordinates the immunological components and cell-to-cell communications of the immune milieu, potentially through the pleiotrophin and the Galectin pathways. In vitro and in vivo evidence support the pro-metastatic role of SMC2 in NSCLC. Subsequent investigations showed that SMC2 increases NSCLC progression and metastasis via modulating the ERK/AKT/NF-κB pathway and the epithelial-mesenchymal transition process. Our research clarifies the role and potential mechanisms of SMC2 in NSCLC, providing new treatment options and valuable insights for the management of NSCLC. Citation Format: Yan He, Zhenyu Luo, Yiyao Wang, Shan Xiong, Rui Wan, Xue Zhang, Hua Bai, Jie Wang. SMC2 orchestrates non-small cell lung cancer proliferation, invasion, and metastasis by modulating the ERK/AKT/NF-κB pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5426.

Sister chromatid cohesion halts DNA loop expansion

Eukaryotic genomes are folded into DNA loops mediated by structural maintenance of chromosomes (SMC) complexes such as cohesin, condensin, and Smc5/6. This organization regulates different DNA-related processes along the cell cycle, such as transcription, recombination, segregation, and DNA repair. During the G2 stage, SMC-mediated DNA loops coexist with cohesin complexes involved in sister chromatid cohesion (SCC). However, the articulation between the establishment of SCC and the formation of SMC-mediated DNA loops along the chromatin remains unknown. Here, we show that SCC is indeed a barrier to cohesin-mediated DNA loop expansion along G2/M Saccharomyces cerevisiae chromosomes.