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F2,6BP restores mitochondrial genome integrity in Huntington's Disease.
bioRxiv
November 2024
Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, 77555, USA.
Several reports have indicated that impaired mitochondrial function contributes to the development and progression of Huntington's disease (HD). Mitochondrial genome damage, particularly DNA strand breaks (SBs), is a potential cause for its compromised functionality. We have recently demonstrated that the activity of polynucleotide kinase 3'-phosphatase (PNKP), a critical DNA end-processing enzyme, is significantly reduced in the nuclear extract of HD patients due to lower level of a metabolite fructose-2,6 bisphosphate (F2,6BP), a biosynthetic product of 6-phosphofructo-2-kinase fructose-2,6-bisphosphatase 3 (PFKFB3), leading to persistent DNA SBs with 3'-phosphate termini, refractory to subsequent steps for repair completion.
View Article and Find Full Text PDFCharacterization of Two Novel PNKP Splice-Site Variants in a Proband With Microcephaly, Intellectual Disability, and Multiple Malformations.
Am J Med Genet B Neuropsychiatr Genet
October 2024
Department of Women's and Children's Health, University of Padova, Padova, Italy.
Polynucleotide kinase phosphatase (PNKP), encoded by the PNKP gene, is a DNA processing enzyme involved in double-strand break and single-strand break repair pathways, which are essential for genome stability and for the correct development and maintenance of human nervous system. PNKP biallelic loss-of-function variants have been associated with a broad spectrum of neurological anomalies, ranging from congenital microcephaly with intellectual disability and seizures (MCSZ), to later onset forms of ataxia-oculomotor apraxia (AOA4) or peripheral neuropathy (CMT2B2). We report the atypical clinical manifestations of a patient with severe microcephaly, short stature, developmental delay, conductive hearing loss, and tracheoesophageal malformation, in the absence of seizures.
View Article and Find Full Text PDFFunctional germline variants in DNA damage repair pathways are associated with altered survival in adults with glioma treated with temozolomide.
medRxiv
October 2024
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
Background: Temozolomide (TMZ) treatment has demonstrated, but variable, impact on glioma prognosis. This study examines associations of survival with DNA repair gene germline polymorphisms among glioma patients who did and did not have TMZ treatment. Identifying genetic markers which sensitize tumor cells to TMZ could personalize therapy and improve outcomes.
View Article and Find Full Text PDFFructose-2,6-bisphosphate restores DNA repair activity of PNKP and ameliorates neurodegenerative symptoms in Huntington's disease.
Proc Natl Acad Sci U S A
September 2024
Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555.
Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3) are the two most prevalent polyglutamine (polyQ) neurodegenerative diseases, caused by CAG (encoding glutamine) repeat expansion in the coding region of the huntingtin (HTT) and ataxin-3 (ATXN3) proteins, respectively. We have earlier reported that the activity, but not the protein level, of an essential DNA repair enzyme, polynucleotide kinase 3'-phosphatase (PNKP), is severely abrogated in both HD and SCA3 resulting in accumulation of double-strand breaks in patients' brain genome. While investigating the mechanistic basis for the loss of PNKP activity and accumulation of DNA double-strand breaks leading to neuronal death, we observed that PNKP interacts with the nuclear isoform of 6-phosphofructo-2-kinase fructose-2,6-bisphosphatase 3 (PFKFB3).
View Article and Find Full Text PDFComprehensive exploration on the role of base excision repair genes in modulating immune infiltration in low-grade glioma.
Pathol Res Pract
October 2024
Human Molecular Genetics Lab, Department of Life Science, National Institute of Technology Rourkela, Odisha 769008, India. Electronic address:
Article Synopsis
- Glioma is a common brain tumour in adults, and despite advancements in understanding it, survival rates and prognostic biomarkers remain insufficient.
- The study analyzed data from public resources, focusing on Base Excision Repair (BER) genes, their role in the tumour microenvironment, and their correlation with immune markers in low-grade glioma (LGG).
- Results indicated that specific BER genes, such as MUTYH, PNKP, UNG, and XRCC1, are linked to immune cells and may serve as prognostic biomarkers, with connections to pathways like Wnt and PD-1 signalling.
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