RIPK4 promotes oxidative stress and ferroptotic death through the downregulation of ACSM1.

One of the most critical axes for cell fate determination is how cells respond to excessive reactive oxygen species (ROS)-oxidative stress. Extensive lipid peroxidation commits cells to death via a distinct cell death paradigm termed ferroptosis. However, the molecular mechanism regulating cellular fates to distinct ROS remains incompletely understood.

Somatic mutations in telomerase promoter counterbalance germline loss-of-function mutations.

Germline coding mutations in different telomere-related genes have been linked to autosomal-dominant familial pulmonary fibrosis. Individuals with these inherited mutations demonstrate incomplete penetrance of clinical phenotypes affecting the lung, blood, liver, skin, and other organs. Here, we describe the somatic acquisition of promoter mutations in telomerase reverse transcriptase (TERT) in blood leukocytes of approximately 5% of individuals with inherited loss-of-function coding mutations in TERT or poly(A)-specific ribonuclease (PARN), another gene linked to telomerase function.

Human polyomavirus 6 and 7 are associated with pruritic and dyskeratotic dermatoses.

Background: Human polyomavirus (HPyV)6 and HPyV7 are shed chronically from human skin. HPyV7, but not HPyV6, has been linked to a pruritic skin eruption of immunosuppression.

Objective: We determined whether biopsy specimens showing a characteristic pattern of dyskeratosis and parakeratosis might be associated with polyomavirus infection.

Glutathione Depletion, Pentose Phosphate Pathway Activation, and Hemolysis in Erythrocytes Protecting Cancer Cells from Vitamin C-induced Oxidative Stress.

The discovery that oxidized vitamin C, dehydroascorbate (DHA), can induce oxidative stress and cell death in cancer cells has rekindled interest in the use of high dose vitamin C (VC) as a cancer therapy. However, high dose VC has shown limited efficacy in clinical trials, possibly due to the decreased bioavailability of oral VC. Because human erythrocytes express high levels of Glut1, take up DHA, and reduce it to VC, we tested how erythrocytes might impact high dose VC therapies.

Nucks1 synergizes with Trp53 to promote radiation lymphomagenesis in mice.

NUCKS1 is a 27 kD vertebrate-specific protein, with a role in the DNA damage response. Here, we show that after 4 Gy total-body X-irradiation, Trp53+/- Nucks1+/- mice more rapidly developed tumors, particularly thymic lymphoma (TL), than Trp53+/- mice. TLs in both cohorts showed loss of heterozygosity (LOH) of the Trp53+ allele in essentially all cases.

Role and fate of SP100 protein in response to Rep-dependent nonviral integration system.

Previously, we studied an AAVS1 site-specific non-viral integration system with a Rep-donor plasmid and a plasmid containing adeno-associated virus integration element. Our earlier study focused on the plasmid vector itself, but the cellular response to the system was still unknown. SP100 is a member of the promyelocytic leukemia nuclear bodies.

Functional differentiation between Rep-mediated site-specific integration and transcriptional repression of the adeno-associated viral p5 promoter.

The adeno-associated virus (AAV) p5 promoter controls expression of Rep68 and Rep78, which are responsible for specific integration of the viral genome into the AAVS1 site of the human genome. The p5 promoter contains a Rep-binding element (RBE) sequence that acts as a substrate of the Rep proteins for both site-specific integration of p5 itself and transcriptional suppression of the p5 promoter. To differentiate these two Rep-mediated functions, we dissected the p5 core structure TATA/RBE/YY1+1 through a series of mutations.

A 16bp Rep binding element is sufficient for mediating Rep-dependent integration into AAVS1.

Adeno-associated virus (AAV) is a non-pathogenic virus and the only known eukaryotic virus capable of targeting human chromosome 19 for integration at a well-characterized AAVS1 site. Its site-specific integration is mediated by Rep68 and Rep78, viral proteins that bind to both the viral genome and AAVS1 site on ch19 through a specific Rep-binding element (RBE) located in both the viral genome and AAVS1. There are three RBEs in the AAV genome: two identical ones in both inverted terminal repeats (ITR) and another one in a recently discovered region termed the P5 integration efficiency element (P5IEE) that encompasses the viral P5 promoter.