The expression and role of the Lem-D proteins Ankle2, Emerin, Lemd2, and TMPO in triple-negative breast cancer cell growth.

Background: Triple-negative breast cancer (TNBC) is a sub-classification of breast carcinomas, which leads to poor survival outcomes for patients. TNBCs do not possess the hormone receptors that are frequently targeted as a therapeutic in other cancer subtypes and, therefore, chemotherapy remains the standard treatment for TNBC. Nuclear envelope proteins are frequently dysregulated in cancer cells, supporting their potential as novel cancer therapy targets.

Targeting the COMMD4-H2B protein complex in lung cancer.

Background: Lung cancer is the biggest cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 85-90% of all lung cancers. Identification of novel therapeutic targets are required as drug resistance impairs chemotherapy effectiveness.

The fructose-bisphosphate, Aldolase A (ALDOA), facilitates DNA-PKcs and ATM kinase activity to regulate DNA double-strand break repair.

Glucose metabolism and DNA repair are fundamental cellular processes frequently dysregulated in cancer. In this study, we define a direct role for the glycolytic Aldolase A (ALDOA) protein in DNA double-strand break (DSB) repair. ALDOA is a fructose biphosphate Aldolase that catalyses fructose-1,6-bisphosphate to glyceraldehyde 3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP), during glycolysis.

Stochastic epithelial-mesenchymal transitions diversify non-cancerous lung cell behaviours.

Epithelial-mesenchymal plasticity (EMP) is a hallmark of cancer. By enabling cells to shift between different morphological and functional states, EMP promotes invasion, metastasis and therapy resistance. We report that near-diploid non-cancerous human epithelial lung cells spontaneously shift along the EMP spectrum without genetic changes.

The role of inner nuclear membrane proteins in tumourigenesis and as potential targets for cancer therapy.

Despite significant advances in our understanding of tumourigenesis and cancer therapeutics, cancer continues to account for 30% of worldwide deaths. Therefore, there remains an unmet need for the development of cancer therapies to improve patient quality of life and survival outcomes. The inner nuclear membrane has an essential role in cell division, cell signalling, transcription, cell cycle progression, chromosome tethering, cell migration and mitosis.

Beyond PARP1: The Potential of Other Members of the Poly (ADP-Ribose) Polymerase Family in DNA Repair and Cancer Therapeutics.

The proteins within the Poly-ADP Ribose Polymerase (PARP) family encompass a diverse and integral set of cellular functions. PARP1 and PARP2 have been extensively studied for their roles in DNA repair and as targets for cancer therapeutics. Several PARP inhibitors (PARPi) have been approved for clinical use, however, while their efficacy is promising, tumours readily develop PARPi resistance.

The Impact of Rare Human Variants on Barrier-To-Auto-Integration Factor 1 (Banf1) Structure and Function.

Barrier-to-Autointegration Factor 1 (Banf1/BAF) is a critical component of the nuclear envelope and is involved in the maintenance of chromatin structure and genome stability. Banf1 is a small DNA binding protein that is conserved amongst multicellular eukaryotes. Banf1 functions as a dimer, and binds non-specifically to the phosphate backbone of DNA, compacting the DNA in a looping process.

Epigenetic Mechanisms in DNA Double Strand Break Repair: A Clinical Review.

Upon the induction of DNA damage, the chromatin structure unwinds to allow access to enzymes to catalyse the repair. The regulation of the winding and unwinding of chromatin occurs via epigenetic modifications, which can alter gene expression without changing the DNA sequence. Epigenetic mechanisms such as histone acetylation and DNA methylation are known to be reversible and have been indicated to play different roles in the repair of DNA.

Elevating CDCA3 levels in non-small cell lung cancer enhances sensitivity to platinum-based chemotherapy.

Platinum-based chemotherapy remains the cornerstone of treatment for most non-small cell lung cancer (NSCLC) cases either as maintenance therapy or in combination with immunotherapy. However, resistance remains a primary issue. Our findings point to the possibility of exploiting levels of cell division cycle associated protein-3 (CDCA3) to improve response of NSCLC tumours to therapy.

COMMD4 functions with the histone H2A-H2B dimer for the timely repair of DNA double-strand breaks.

Genomic stability is critical for normal cellular function and its deregulation is a universal hallmark of cancer. Here we outline a previously undescribed role of COMMD4 in maintaining genomic stability, by regulation of chromatin remodelling at sites of DNA double-strand breaks. At break-sites, COMMD4 binds to and protects histone H2B from monoubiquitination by RNF20/RNF40.

Barrier-to-autointegration-factor (Banf1) modulates DNA double-strand break repair pathway choice via regulation of DNA-dependent kinase (DNA-PK) activity.

DNA repair pathways are essential to maintain the integrity of the genome and prevent cell death and tumourigenesis. Here, we show that the Barrier-to-Autointegration Factor (Banf1) protein has a role in the repair of DNA double-strand breaks. Banf1 is characterized as a nuclear envelope protein and mutations in Banf1 are associated with the severe premature aging syndrome, Néstor-Guillermo Progeria Syndrome.

SASH1 is a prognostic indicator and potential therapeutic target in non-small cell lung cancer.

SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor protein that has roles in key cellular processes including apoptosis and cellular proliferation. As these cellular processes are frequently disrupted in human tumours and little is known about the role of SASH1 in the pathogenesis of the disease, we analysed the prognostic value of SASH1 in non-small cell lung cancers using publicly available datasets. Here, we show that low SASH1 mRNA expression is associated with poor survival in adenocarcinoma.

PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance.

The Poly (ADP-ribose) polymerase (PARP) family has many essential functions in cellular processes, including the regulation of transcription, apoptosis and the DNA damage response. PARP1 possesses Poly (ADP-ribose) activity and when activated by DNA damage, adds branched PAR chains to facilitate the recruitment of other repair proteins to promote the repair of DNA single-strand breaks. PARP inhibitors (PARPi) were the first approved cancer drugs that specifically targeted the DNA damage response in BRCA1/2 mutated breast and ovarian cancers.

The Therapeutic Potential of DNA Damage Repair Pathways and Genomic Stability in Lung Cancer.

Despite advances in our understanding of the molecular biology of the disease and improved therapeutics, lung cancer remains the most common cause of cancer-related deaths worldwide. Therefore, an unmet need remains for improved treatments, especially in advanced stage disease. Genomic instability is a universal hallmark of all cancers.

Barrier-to-autointegration factor 1 (Banf1) regulates poly [ADP-ribose] polymerase 1 (PARP1) activity following oxidative DNA damage.

The DNA repair capacity of human cells declines with age, in a process that is not clearly understood. Mutation of the nuclear envelope protein barrier-to-autointegration factor 1 (Banf1) has previously been shown to cause a human progeroid disorder, Néstor-Guillermo progeria syndrome (NGPS). The underlying links between Banf1, DNA repair and the ageing process are unknown.

Bead-linked transposomes enable a normalization-free workflow for NGS library preparation.

Background: Transposome-based technologies have enabled the streamlined production of sequencer-ready DNA libraries; however, current methods are highly sensitive to the amount and quality of input nucleic acid.

Results: We describe a new library preparation technology (Nextera DNA Flex) that utilizes a known concentration of transposomes conjugated directly to beads to bind a fixed amount of DNA, and enables direct input of blood and saliva using an integrated extraction protocol. We further report results from libraries generated outside the standard parameters of the workflow, highlighting novel applications for Nextera DNA Flex, including human genome builds and variant calling from below 1 ng DNA input, customization of insert size, and preparation of libraries from short fragments and severely degraded FFPE samples.

Expression of CDCA3 Is a Prognostic Biomarker and Potential Therapeutic Target in Non-Small Cell Lung Cancer.

Introduction: NSCLC is the leading cause for cancer-related deaths worldwide. New therapeutic targets are needed, as development of resistance to current treatment, such as platinum-based chemotherapy, is inevitable. The purpose of this study was to determine the functional relevance and therapeutic potential of cell division cycle associated 3 protein (CDCA3) in NSCLC.

Activation and cleavage of SASH1 by caspase-3 mediates an apoptotic response.

Apoptosis is a highly regulated cellular process that functions to remove undesired cells from multicellular organisms. This pathway is often disrupted in cancer, providing tumours with a mechanism to avoid cell death and promote growth and survival. The putative tumour suppressor, SASH1 (SAM and SH3 domain containing protein 1), has been previously implicated in the regulation of apoptosis; however, the molecular role of SASH1 in this process is still unclear.

SASH1 mediates sensitivity of breast cancer cells to chloropyramine and is associated with prognosis in breast cancer.

Expression of the SASH1 protein is reduced in a range of human cancers and has been implicated in apoptotic cancer cell death. This study investigated whether increasing SASH1 expression could be a useful therapeutic strategy in breast cancer. Ectopic SASH1 expression increased apoptosis in 7/8 breast cancer cell lines.

hSSB1 (NABP2/ OBFC2B) is required for the repair of 8-oxo-guanine by the hOGG1-mediated base excision repair pathway.

The maintenance of genome stability is essential to prevent loss of genetic information and the development of diseases such as cancer. One of the most common forms of damage to the genetic code is the oxidation of DNA by reactive oxygen species (ROS), of which 8-oxo-7,8-dihydro-guanine (8-oxoG) is the most frequent modification. Previous studies have established that human single-stranded DNA-binding protein 1 (hSSB1) is essential for the repair of double-stranded DNA breaks by the process of homologous recombination.

Pneumocystis carinii interactions with lung epithelial cells and matrix proteins induce expression and activity of the PcSte20 kinase with subsequent phosphorylation of the downstream cell wall biosynthesis kinase PcCbk1.

Eukaryotic cell proliferation and phenotype are highly regulated by contact-dependent mechanisms. We have previously shown that the binding and interaction of the opportunistic fungal pathogen Pneumocystis carinii to lung epithelial cells and extracellular matrix proteins induces mRNA expression of both the mitogen-activated protein (MAP) kinase P. carinii Ste20 (PcSte20) and the cell wall-remodeling enzyme PcCbk1 (16).

Non-rural point source blastomycosis outbreak near a yard waste collection site.

Background: Blastomycosis is a potentially fatal infection caused by the fungus Blastomyces dermatitidis. During January 1 through March 5, 2006, twenty-one laboratory confirmed cases of blastomycosis were reported among residents of an endemic area in north-central Wisconsin; a striking increase compared with previous years. The objective of the study was to determine if an observed increase in blastomycosis among residents of an urban area in north-central Wisconsin was caused by a point-source exposure and to identify its source.

The Pneumocystis meiotic PCRan1p kinase exhibits unique temperature-regulated activity.

Pneumocystis organisms are opportunistic fungal pathogens that cause significant pneumonia in immune-compromised hosts. Recent evidence has suggested that Pneumocystis carinii exists as separate mating types, and expresses and regulates proteins that govern meiosis and progression of the life cycle. This study was undertaken to investigate the activity of three life cycle-regulatory proteins in Pneumocystis, including two proteins essential in mating signaling, and a putative meiotic regulator, to determine the conditions under which they are most active.

Pneumocystis carinii exhibits a conserved meiotic control pathway.

Pneumocystis carinii is an opportunistic fungus causing severe pneumonia in immune-compromised hosts. Recent evidence suggests that Pneumocystis exists as separate sex types, though definitive evidence is currently lacking. These studies were undertaken to determine whether Pneumocystis maintains functional meiotic control molecules, which are required for sexual life stages in eukaryotes.