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R-Loop-Mediated ssDNA Breaks Accumulate Following Short-Term Exposure to the HDAC Inhibitor Romidepsin.
Safari, Maryam; Litman, Thomas; Robey, Robert W; Aguilera, Andrés; Chakraborty, Arup R; Reinhold, William C; Basseville, Agnes; Petrukhin, Lubov; Scotto, Luigi; O'Connor, Owen A; Pommier, Yves; Fojo, Antonio T; Bates, Susan E.
Afiliação
  • Safari M; Division of Hematology and Oncology, Department of Medicine, Columbia University, New York, New York.
  • Litman T; University of Copenhagen, Copenhagen, Denmark.
  • Robey RW; Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
  • Aguilera A; Centro Andaluz de Biología Molecular y Medicina Regenerativa, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Seville, Spain.
  • Chakraborty AR; Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
  • Reinhold WC; Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
  • Basseville A; Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
  • Petrukhin L; Bioinfomics Unit, Institut de Cancérologie de l'Ouest, Saint Herblain, France.
  • Scotto L; Division of Hematology and Oncology, Department of Medicine, Columbia University, New York, New York.
  • O'Connor OA; Center for Lymphoid Malignancies, Columbia University, New York, New York.
  • Pommier Y; Department of Medicine, University of Virginia, Charlottesville, Virginia.
  • Fojo AT; Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
  • Bates SE; Division of Hematology and Oncology, Department of Medicine, Columbia University, New York, New York.
Mol Cancer Res ; 19(8): 1361-1374, 2021 08.
Article em En | MEDLINE | ID: mdl-34050002
ABSTRACT
Histone deacetylase inhibitors (HDACi) induce hyperacetylation of histones by blocking HDAC catalytic sites. Despite regulatory approvals in hematological malignancies, limited solid tumor clinical activity has constrained their potential, arguing for better understanding of mechanisms of action (MOA). Multiple activities of HDACis have been demonstrated, dependent on cell context, beyond the canonical induction of gene expression. Here, using a clinically relevant exposure duration, we established DNA damage as the dominant signature using the NCI-60 cell line database and then focused on the mechanism by which hyperacetylation induces DNA damage. We identified accumulation of DNA-RNA hybrids (R-loops) following romidepsin-induced histone hyperacetylation, with single-stranded DNA (ssDNA) breaks detected by single-cell electrophoresis. Our data suggest that transcription-coupled base excision repair (BER) is involved in resolving ssDNA breaks that, when overwhelmed, evolve to lethal dsDNA breaks. We show that inhibition of BER proteins such as PARP will increase dsDNA breaks in this context. These studies establish accumulation of R-loops as a consequence of romidepsin-mediated histone hyperacetylation. We believe that the insights provided will inform design of more effective combination therapy with HDACis for treatment of solid tumors. IMPLICATIONS Key HDAC inhibitor mechanisms of action remain unknown; we identify accumulation of DNA-RNA hybrids (R-loops) due to chromatin hyperacetylation that provokes single-stranded DNA damage as a first step toward cell death.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: DNA de Cadeia Simples / Depsipeptídeos / Inibidores de Histona Desacetilases / Estruturas R-Loop / Histona Desacetilases Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: DNA de Cadeia Simples / Depsipeptídeos / Inibidores de Histona Desacetilases / Estruturas R-Loop / Histona Desacetilases Idioma: En Ano de publicação: 2021 Tipo de documento: Article