DNA polymerase (DNAP) is a dual-purpose enzyme that plays two opposite roles in two different situations during DNA replication. It plays its a normal role as a polymerase catalyzing the elongation of a new DNA molecule by adding a monomer. However, it can switch to the role of an exonuclease and shorten the same DNA by cleavage of the last incorporated monomer from the nascent DNA. Just as misincorporated nucleotides can escape exonuclease causing a replication error, the correct nucleotide may get sacrificed unnecessarily by erroneous cleavage. The interplay of polymerase and exonuclease activities of a DNAP is explored here by developing a minimal stochastic kinetic model of DNA replication. Exact analytical expressions are derived for a few key statistical distributions; these characterize the temporal patterns in the mechanical stepping and the chemical (cleavage) reaction. The Michaelis-Menten-like analytical expression derived for the average rates of these two processes not only demonstrate the effects of their coupling, but are also utilized to measure the extent of replication error and erroneous cleavage.
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http://dx.doi.org/10.1103/PhysRevE.86.011913 | DOI Listing |
Cell Death Discov
January 2025
Laboratory of Genome Stress Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan.
DNA replication stress (RS), a prevalent feature of various malignancies, arises from both genetic mutations and genotoxic exposure. Elevated RS levels increase the vulnerability of cancer cells to ataxia telangiectasia and Rad3-related kinase inhibitors (ATRis). Here, we screened for DNA damage response inhibitors that enhance ATRi-induced cytotoxicity using SWI/SNF complex-deficient cells and identified a potent synergy between ATRi and poly(ADP-ribose) polymerase inhibitor (PARPi), particularly in SMARCA4-deficient cells.
View Article and Find Full Text PDFSci Total Environ
January 2025
School of Environmental Science and Engineering, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Provincial Key Laboratory of Environmental Pollution Control and Remediation Technology, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou 510006, China. Electronic address:
Cadmium (Cd) pollution is a global concern. Protists represent a prevalent yet understudied group in soil ecosystems, but our understanding of how protists interact with Cd remains limited. This study investigates the interaction between Cd and the soil amoeba Dictyostelium discoideum, focusing on its resistance, accumulation, and molecular mechanisms.
View Article and Find Full Text PDFCancer Genet
January 2025
Department of Chemistry and Biochemistry, The Ohio State University, Marion, USA. Electronic address:
DNA double strand breaks (DSBs) can be generated spontaneously during DNA replication and are repaired primarily by Homologous Recombination (HR). However, efficient repair requires chromatin remodeling to allow the recombination machinery access to the break. TIP60 is a complex conserved from yeast to humans that is required for histone acetylation and modulation of HR activity at DSBs.
View Article and Find Full Text PDFCarcinogenesis
January 2025
Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA.
Endometrial cancer [EC] is the fourth most common cancer in women in the United States. Stark racial disparities are present in EC outcomes in which Black women have significantly higher EC-related mortality than White women. The social and biologic factors that contribute to these disparities are complex, and may include racial differences in epigenetic landscapes.
View Article and Find Full Text PDFOpen Forum Infect Dis
January 2025
CHU d'Orléans, Orléans, France.
Background: To better understand factors associated with virologic response, we retrospectively characterized the HIV proviruses of 7 people with HIV who received long-acting cabotegravir/rilpivirine (CAB/RPV-LA) and were selected according to the following criteria: virologic control achieved despite a history of viral replication on 1 or both corresponding antiretroviral classes (n = 6) and virologic failure (VF) after CAB/RPV-LA initiation (n = 1).
Methods: Last available blood samples before the initiation of CAB/RPV-LA were analyzed retrospectively. Near full-length HIV DNA genome haplotypes were inferred from Nanopore sequencing by the in vivo Genome Diversity Analyzer to search for archived drug resistance mutations (DRMs) and evaluate the frequency and intactness of proviruses harboring DRMs.
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