POLH and POLI are paralogs encoding low-fidelity, class Y, DNA polymerases involved in replication of damaged DNA in the human disease xeroderma pigmentosum variant. Analysis of genomic regions for human and mouse homologs, employing the analytic tool Genome Cryptographer, detected low-repetitive or unique regions at exons and other potential control regions, especially within intron I of human POLH. The human and mouse homologs are structurally similar, but the paralogs have undergone evolutionary divergence. The information content of splice sites for human POLH, the probability that a base would contribute to splicing, was low only for the acceptor site of exon II, which is preceded by a region of high information content that could contain sequences controlling splicing. This analysis explains previous observations of tissue-specific skipping during mRNA processing, resulting in the loss of the transcription start site in exon II, in human tissues.
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http://dx.doi.org/10.1016/s0888-7543(03)00180-0 | DOI Listing |
Nat Commun
January 2025
Sorbonne Université, CNRS, Laboratory of Computational and Quantitative Biology, LCQB, Paris, France.
Telomere shortening ultimately causes replicative senescence. However, identifying the mechanisms driving replicative senescence in cell populations is challenging due to the heterogeneity of telomere lengths and the asynchrony of senescence onset. Here, we present a mathematical model of telomere shortening and replicative senescence in Saccharomyces cerevisiae which is quantitatively calibrated and validated using data of telomerase-deficient single cells.
View Article and Find Full Text PDFNat Commun
January 2025
Robson DNA Science Centre, Charbonneau Cancer Institute, Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
To tolerate oxidative stress, cells enable DNA repair responses often sensitive to poly(ADP-ribose) (PAR) polymerase 1 and 2 (PARP1/2) inhibition-an intervention effective against cancers lacking BRCA1/2. Here, we demonstrate that mutating the CHD6 chromatin remodeler sensitizes cells to PARP1/2 inhibitors in a manner distinct from BRCA1, and that CHD6 recruitment to DNA damage requires cooperation between PAR- and DNA-binding domains essential for nucleosome sliding activity. CHD6 displays direct PAR-binding, interacts with PARP-1 and other PAR-associated proteins, and combined DNA- and PAR-binding loss eliminates CHD6 relocalization to DNA damage.
View Article and Find Full Text PDFJ Biol Chem
January 2025
Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, Quebec H3A 1A3, Canada; Department of Medicine, McGill University, Montreal, Quebec H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, Quebec H3A 1A3, Canada; McGill University Health Center, Montreal, Quebec H3A 1A3, Canada. Electronic address:
Site-directed mutagenesis is a fundamental tool indispensable for protein and plasmid engineering. An important technological question is how to achieve the efficiency at the ideal level of 100%. Based on complementary primer pairs, the QuickChange method has been widely used, but it requires significant improvements due to its low efficiency and frequent unwanted mutations.
View Article and Find Full Text PDFMol Biol Rep
January 2025
Department of Integrative Biology, School of Bio-Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.
Telomerase, constituted by the dynamic duo of telomerase reverse transcriptase (TERT), the catalytic entity, and an integral RNA component (TERC), is predominantly suppressed in differentiated human cells due to postnatal transcriptional repression of the TERT gene. Dysregulation of telomerase significantly contributes to cancer development via telomere-dependent and independent mechanisms. Telomerase activity is often elevated in advanced cancers, with TERT reactivation and upregulation of TERC observed in early tumorigenesis.
View Article and Find Full Text PDFViruses
January 2025
Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management, Yaoundé P.O. Box 3077, Cameroon.
Islatravir (ISL) is a novel antiretroviral that inhibits HIV-1 reverse transcriptase translocation. The M184V mutation, known to reduce ISL's viral susceptibility in vitro, could arise from prolonged exposure to nucleoside reverse transcriptase inhibitors (NRTI) (3TC). This study evaluated the predictive efficacy of ISL and identified potentially active antiretrovirals in combination among treatment-experienced patients in Cameroon, where NRTIs (3TC) have been the backbone of ART for decades now.
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