Article ; Online: R-Loop-Mediated ssDNA Breaks Accumulate Following Short-Term Exposure to the HDAC Inhibitor Romidepsin.
Molecular cancer research : MCR
2021 Volume 19, Issue 8, Page(s) 1361–1374
Abstract: ... by which hyperacetylation induces DNA damage. We identified accumulation of DNA-RNA hybrids (R-loops) following romidepsin ... proteins such as PARP will increase dsDNA breaks in this context. These studies establish accumulation of R ... hybrids (R-loops) due to chromatin hyperacetylation that provokes single-stranded DNA damage as a first ...
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. |
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MeSH term(s) | Acetylation/drug effects ; Cell Line, Tumor ; DNA Damage/drug effects ; DNA Damage/genetics ; DNA Repair/drug effects ; DNA Repair/genetics ; DNA, Single-Stranded/drug effects ; DNA, Single-Stranded/genetics ; Depsipeptides/pharmacology ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylases/metabolism ; Humans ; PC-3 Cells ; R-Loop Structures/drug effects ; R-Loop Structures/genetics |
Chemical Substances | DNA, Single-Stranded ; Depsipeptides ; Histone Deacetylase Inhibitors ; romidepsin (CX3T89XQBK) ; Histone Deacetylases (EC 3.5.1.98) |
Language | English |
Publishing date | 2021-05-28 |
Publishing country | United States |
Document type | Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't |
ZDB-ID | 2098788-2 |
ISSN | 1557-3125 ; 1541-7786 |
ISSN (online) | 1557-3125 |
ISSN | 1541-7786 |
DOI | 10.1158/1541-7786.MCR-20-0833 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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