Repeat expansion in a Fragile X model is independent of double strand break repair mediated by Pol θ, Rad52, Rad54l or Rad54b.

Microsatellite instability is responsible for the human Repeat Expansion Disorders. The mutation responsible differs from classical cancer-associated microsatellite instability (MSI) in that it requires the mismatch repair proteins that normally protect against MSI. LIG4, an enzyme essential for non-homologous end-joining (NHEJ), the major pathway for double-strand break repair (DSBR) in mammalian cells, protects against expansion in mouse models.

Sleep-Related Hypoxia, Right Ventricular Dysfunction, and Survival in Patients With Group 1 Pulmonary Arterial Hypertension.

Background: Group 1 pulmonary arterial hypertension (PAH) is a progressive fatal condition characterized by right ventricular (RV) failure with worse outcomes in connective tissue disease (CTD). Obstructive sleep apnea and sleep-related hypoxia may contribute to RV dysfunction, though the relationship remains unclear.

Objectives: The aim of this study was to prospectively evaluate the association of the apnea-hypopnea index (AHI) and sleep-related hypoxia with RV function and survival.

Personalized multimodal management for severe obstructive sleep apnea in a patient intolerant of positive airway pressure with hypoglossal nerve stimulator and mandibular advancement device.

Unlabelled: Treatment of moderate to severe obstructive sleep apnea poses clinical challenges in persons with intolerance or inadequate response to traditional treatment modalities, including positive airway pressure and mandibular advancement devices. Hypoglossal nerve stimulation is a new treatment option, but few management guidelines exist when it is intolerable or ineffective. Combining several treatment modalities has been an effective strategy for improving symptoms, tolerance, and efficacy.

Atypical Variant of Guillain Barre Syndrome in a Patient with COVID-19.

Objective: A rare variant Miller Fisher Syndrome overlap with Guillain Barre Syndrome is described in an adult patient with SARS-COV-2 infection.

Case Presentation: The clinical course of a 45-year-old immunosuppressed man is summarized as a patient who developed ataxia, ophthalmoplegia, and areflexia after upper respiratory infection symptoms began. A nasopharyngeal swab was positive for COVID-19 polymerase chain reaction.

Brain lesion in a recreational drug user: Isolated cerebral mucormycosis.

Isolated cerebral mucormycosis is a relatively rare and unique variant of mucormycosis which is seen most commonly in patients with intravenous recreational drug use. While this invasive fungal infection in the brain is thought to spread from the sinuses or the lungs in other hosts such as diabetics and those with malignancy, hematogenous spread and seeding has been attributed in the pathogenesis of isolated cerebral mucormycosis. Clinical features and radiological findings may be non-specific and hence, heightened clinical suspicion for a prompt diagnosis and early medical and surgical intervention is paramount for a favorable outcome in such rare, but potentially fatal infections.

Transcriptional consequences of XPA disruption in human cell lines.

Nucleotide excision repair (NER) in mammalian cells requires the xeroderma pigmentosum group A protein (XPA) as a core factor. Remarkably, XPA and other NER proteins have been detected by chromatin immunoprecipitation at some active promoters, and NER deficiency is reported to influence the activated transcription of selected genes. However, the global influence of XPA on transcription in human cells has not been determined.

Analysis of DNA polymerase ν function in meiotic recombination, immunoglobulin class-switching, and DNA damage tolerance.

DNA polymerase ν (pol ν), encoded by the POLN gene, is an A-family DNA polymerase in vertebrates and some other animal lineages. Here we report an in-depth analysis of pol ν-defective mice and human cells. POLN is very weakly expressed in most tissues, with the highest relative expression in testis.

The homologous recombination protein RAD51D protects the genome from large deletions.

Homologous recombination (HR) is a DNA double-strand break (DSB) repair pathway that protects the genome from chromosomal instability. RAD51 mediator proteins (i.e.

Modularized functions of the Fanconi anemia core complex.

The Fanconi anemia (FA) core complex provides the essential E3 ligase function for spatially defined FANCD2 ubiquitination and FA pathway activation. Of the seven FA gene products forming the core complex, FANCL possesses a RING domain with demonstrated E3 ligase activity. The other six components do not have clearly defined roles.

Structure analysis of FAAP24 reveals single-stranded DNA-binding activity and domain functions in DNA damage response.

The FANCM/FAAP24 heterodimer has distinct functions in protecting cells from complex DNA lesions such as interstrand crosslinks. These functions rely on the biochemical activity of FANCM/FAAP24 to recognize and bind to damaged DNA or stalled replication forks. However, the DNA-binding activity of this complex was not clearly defined.

FANCM and FAAP24 maintain genome stability via cooperative as well as unique functions.

The DNA remodeling enzyme FANCM and its DNA-binding partner, FAAP24, constitute a complex involved in the activation of Fanconi anemia (FA) DNA damage response mechanism, but neither gene has distinct patient mutants. In this study, we created isogenic models for both FANCM and FAAP24 and investigated their integrated functions in DNA damage response. We found that FANCM and FAAP24 coordinately facilitate FA pathway activation and suppress sister chromatid exchange.

Effects of varying gene targeting parameters on processing of recombination intermediates by ERCC1-XPF.

The ERCC1-XPF structure-specific endonuclease is necessary for correct processing of homologous recombination intermediates requiring the removal of end-blocking nonhomologies. We previously showed that targeting the endogenous CHO APRT locus with plasmids designed to generate such intermediates revealed defective recombination phenotypes in ERCC1 deficient cells, including suppression of targeted insertion and vector correction recombinants and the generation of a novel class of aberrant recombinants through a deletogenic mechanism. In the present study, we examined some of the mechanistic features of ERCC1-XPF in processing recombination intermediates by varying gene targeting parameters.

Depletion of Werner helicase results in mitotic hyperrecombination and pleiotropic homologous and nonhomologous recombination phenotypes.

Werner syndrome (WS) is a rare, segmental progeroid syndrome caused by defects in the WRN gene, which encodes a RecQ helicase. WRN has roles in many aspects of DNA metabolism including DNA repair and recombination. In this study, we exploited two different recombination assays previously used to describe a role for the structure-specific endonuclease ERCC1-XPF in mitotic and targeted homologous recombination.

Characterization of CHO XPF mutant UV41: influence of XPF heterozygosity on double-strand break-induced intrachromosomal recombination.

The UV hypersensitive CHO cell mutant UV41 is the archetypal XPF mammalian cell mutant, and was essential for cloning the human nucleotide excision repair (NER) gene XPF by DNA transfection and rescue. The ERCC1 and XPF genes encode proteins that form the heterodimer responsible for making incisions required in NER and the processing of certain types of recombination intermediates. In this study, we cloned and sequenced the CHO cell XPF cDNA, determining that the XPF mutation in UV41 is a +1 insertion in exon 8 generating a premature stop codon at amino acid position 499; however, the second allele of XPF is apparently unaltered in UV41, resulting in XPF heterozygosity.

Impact of p210(Bcr-Abl) on ultraviolet C wavelength-induced DNA damage and repair.

Recently, it was shown that both Bcr and Bcr-Abl can interact with xeroderma pigmentosum group B (XPB/ERCC3), a protein implicated in DNA repair after UV-induced damage. To further analyze the effect of Bcr-Abl on the DNA damage response, we used cell lines stably transfected with the BCR-ABL gene and their parental counterparts (MBA-1 versus MO7E and Bcr-AblT1 versus 4A2(+)-pZAP) and several assays reflecting DNA repair: the comet assay, a radioimmunoassay for cyclobutane pyrimidine dimers, and clonogenic assays. After exposure to UVC (0.

Mechanisms underlying DNA damage resistance in a Xiphophorus melanoma cell line.

The Xiphophorus hybrid fish model is an important resource for investigating the genetics and molecular biology of melanoma. Consistent with studies using human melanoma cell lines, the Xiphophorus melanoma cell line PSM, survives the lethal effects of ultraviolet-B radiation (UV-B) radiation much better than a cell line derived from normal fish tissue. In contrast to human melanoma cells, which show enhanced nucleotide excision repair, we do not see any differences in the efficiencies of photoenzymatic or nucleotide excision repair in normal and melanoma cell lines.