Publications by authors named "R A Pomerantz"
A route to prepare ribonucleoside triphosphates featuring a 3'-aminoxy (3'-O-NH ) removable blocking group is reported here. We then show that versions of two DNA polymerases, human DNA polymerase theta (Polθ) and mimiviral PrimPol, accept these triphosphates as substrates to add single nucleotides to an RNA primer under engineered conditions. Cleaving the O-N bond in the 3'-O-NH group within the extended primer regenerates the 3'-OH group, facilitating subsequent polymerase cycles that add a second, selected, nucleotide.
View Article and Find Full Text PDFMyeloid malignancies carrying somatic DNMT3A mutations (DNMT3Amut) are usually resistant to standard therapy. DNMT3Amut leukemia cells accumulate toxic DNA double strand breaks (DSBs) and collapsed replication forks, rendering them dependent on DNA damage response (DDR). DNA polymerase theta (Polθ), a key element in Polθ-mediated DNA end-joining (TMEJ), is essential for survival and proliferation of DNMT3Amut leukemia cells.
View Article and Find Full Text PDFDNA polymerase theta (Polθ) is a DNA helicase-polymerase protein that facilitates DNA repair and is synthetic lethal with homology-directed repair (HDR) factors. Thus, Polθ is a promising precision oncology drug-target in HDR-deficient cancers. Here, we characterize the binding and mechanism of action of a Polθ helicase (Polθ-hel) small-molecule inhibitor (AB25583) using cryo-EM.
View Article and Find Full Text PDFArticle Synopsis
- DNA polymerase theta (Polθ) is a protein involved in repairing DNA double-strand breaks and helps cells resist harmful agents.
- The regulation of Polθ's activity in this repair process, known as TMEJ (Theta-Mediated End Joining), involves a two-step mechanism where PARP1 first attaches a modification (PARylation) to Polθ, bringing it to damage sites but rendering it inactive.
- The enzyme PARG then removes this modification, restoring Polθ's ability to bind DNA and perform the repair, making PARG crucial for the activation of TMEJ in response to DNA damage.
DNA double-strand breaks (DSBs) present a critical threat to genomic integrity, often precipitating genomic instability and oncogenesis. Repair of DSBs predominantly occurs through homologous recombination (HR) and non-homologous end joining (NHEJ). In HR-deficient cells, DNA polymerase theta (Polθ) becomes critical for DSB repair via microhomology-mediated end joining (MMEJ), also termed theta-mediated end joining (TMEJ).
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