<oai_dc:dc xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:oai_dc="http://www.openarchives.org/OAI/2.0/oai_dc/" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xsi:schemaLocation="http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd">
  <dc:rights>http://creativecommons.org/licenses/by-nc-nd/4.0/</dc:rights>
  <dc:format>application/pdf</dc:format>
  <dc:subject xml:lang="eng">DNA Polymerase Theta</dc:subject>
  <dc:subject xml:lang="eng">DNMT3A-deficient Acute Myeloid Leukemia</dc:subject>
  <dc:subject xml:lang="eng">PARP1</dc:subject>
  <dc:subject xml:lang="eng">TMEJ</dc:subject>
  <dc:subject xml:lang="eng">Replication Fork</dc:subject>
  <dc:subject xml:lang="eng">Ubiquitination</dc:subject>
  <dc:title xml:lang="eng">Polθ activity modulates sensitivity to standard therapies in DNMT3A-deficient leukemia</dc:title>
  <dc:description xml:lang="eng">Myeloid malignancies carrying somatic DNMT3A mutations (DNMT3Amut) are refractory to standard therapy. DNMT3Amut leukemia cells accumulate toxic DNA double-strand breaks (DSBs) and stalled replication forks, rendering them dependent on DNA damage response (DDR). We report here that DNA polymerase theta (Polθ), a key element in DSB repair by end-joining (Polθ-mediated end-joining [TMEJ]) and in fork restarting, promotes survival and proliferation of DNMT3Amut leukemia cells. Polθ is overexpressed in DNMT3Amut leukemia cells due to abrogation of PARP1 PARylation-dependent UBE2O E3 ligase-mediated ubiquitination and proteasomal degradation of Polθ. In addition, PARP1-mediated recruitment of the SMARCAD1-MSH2/MSH3 repressive complex to DSBs is diminished in DNMT3Amut leukemia cells, which facilitates association of Polθ with DNA damage. Polθ inhibitors enhance the anti-leukemic effects of standard drugs such as FLT3 kinase inhibitor quizartinib, cytarabine ± doxorubicin, and etoposide in vitro and in mice with DNMT3Amut leukemia. Altogether, Polθ is an attractive target in DNMT3Amut hematological malignancies.</dc:description>
  <dc:rights xml:lang="ita">Open Access</dc:rights>
  <dc:type xml:lang="deu">Text</dc:type>
  <dc:type xml:lang="deu">Wissenschaftlicher Artikel</dc:type>
  <dc:language>eng</dc:language>
  <dc:identifier>doi:10.1016/j.xcrm.2026.102687</dc:identifier>
  <dc:type xml:lang="eng">Text</dc:type>
  <dc:type xml:lang="eng">journal article</dc:type>
  <dc:source xml:lang="eng">Cell Reports Medicine</dc:source>
  <dc:date>2026</dc:date>
  <dc:rights xml:lang="eng">© 2026 The Author(s)</dc:rights>
  <dc:rights xml:lang="eng">open access</dc:rights>
  <dc:publisher>Elsevier</dc:publisher>
  <dc:creator>Bac Viet Le</dc:creator>
  <dc:creator>Umeshkumar Vekariya</dc:creator>
  <dc:creator>Monika M. Toma</dc:creator>
  <dc:creator>Margaret Nieborowska-Skorska</dc:creator>
  <dc:creator>Marie-Christine Caron</dc:creator>
  <dc:creator>Malgorzata Gozdecka</dc:creator>
  <dc:creator>Zayd Haydar</dc:creator>
  <dc:creator>Martin Walsh</dc:creator>
  <dc:creator>Jayashri Ghosh</dc:creator>
  <dc:creator>Elaine Vaughan-Williams</dc:creator>
  <dc:creator>Paulina Podszywalow-Bartnicka</dc:creator>
  <dc:creator>Anna-Mariya Kukuyan</dc:creator>
  <dc:creator>Sylwia Ziolkowska</dc:creator>
  <dc:creator>Jessica Atkins</dc:creator>
  <dc:creator>Emir Hadzijusufovic (Clinical Centre for Small Animal Health and Research, Clinical Department for Small Animals and Horses, Departments, University of Veterinary Medicine Vienna)</dc:creator>
  <dc:creator>Gurushankar Chandramouly</dc:creator>
  <dc:creator>Reza Nejati</dc:creator>
  <dc:creator>Katarzyna Piwocka</dc:creator>
  <dc:creator>Richard Pomerantz</dc:creator>
  <dc:creator>George S. Vassiliou</dc:creator>
  <dc:creator>Brian J.P. Huntly</dc:creator>
  <dc:creator>Peter Valent</dc:creator>
  <dc:creator>Mariusz Wasik</dc:creator>
  <dc:creator>Alfonso Bellacosa</dc:creator>
  <dc:creator>Jean-Yves Masson</dc:creator>
  <dc:creator>Gaorav P. Gupta</dc:creator>
  <dc:creator>Grant A. Challen</dc:creator>
  <dc:creator>Tomasz Skorski</dc:creator>
  <dc:type xml:lang="ita">Documento PDF</dc:type>
  <dc:type xml:lang="ita">Articolo scientifico</dc:type>
  <dc:identifier>https://phaidra.vetmeduni.ac.at/o:5434</dc:identifier>
</oai_dc:dc>