Cited by 296DNA Repair MechanismsPARP inhibition in cancer therapyEpigenetics and DNA Methylation

Nuclear Acetyl-CoA Production by ACLY Promotes Homologous Recombination

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Sivanand, Sharanya, Rhoades, Seth, Jiang, Qinqin, Lee, Joyce V., Benci, Joseph, Zhang, Jingwen, Yuan, Salina, Viney, Isabella +7 more·2017·Molecular Cell

Abstract

While maintaining the integrity of the genome and sustaining bioenergetics are both fundamental functions of the cell, potential crosstalk between metabolic and DNA repair pathways is poorly understood. Since histone acetylation plays important roles in DNA repair and is sensitive to the availability of acetyl coenzyme A (acetyl-CoA), we investigated a role for metabolic regulation of histone acetylation during the DNA damage response. In this study, we report that nuclear ATP-citrate lyase (ACLY) is phosphorylated at S455 downstream of ataxia telangiectasia mutated (ATM) and AKT following DNA damage. ACLY facilitates histone acetylation at double-strand break (DSB) sites, impairing 53BP1 localization and enabling BRCA1 recruitment and DNA repair by homologous recombination. ACLY phosphorylation and nuclear localization are necessary for its role in promoting BRCA1 recruitment. Upon PARP inhibition, ACLY silencing promotes genomic instability and cell death. Thus, the spatial and temporal control of acetyl-CoA production by ACLY participates in the mechanism of DNA repair pathway choice.

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Crossref · 10.1016/j.molcel.2017.06.008

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Authors
Sivanand, S., Rhoades, S., Jiang, Q., Lee, J. V., Benci, J., Zhang, J., Yuan, S., Viney, I., Zhao, S., Carrer, A., Bennett, M. J., Minn, A. J., Weljie, A. M., Greenberg, R. A., & Wellen, K. E.
Affiliations
  • University of Pennsylvania (US)
  • Children's Hospital of Philadelphia (US)
Corresponding author
Wellen, Kathryn E.
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2017-07
Volume
67
Issue
2
Pages
252-265.e6
ISSN
1097-2765 (ISSN-L)
OpenAlex
W2724987585
Cited by
295
References
67
Citations by year
2026: 36 · 2025: 40 · 2024: 47 · 2023: 30 · 2022: 28 · 2021: 36 · 2020: 29 · 2019: 19 · 2018: 23 · 2017: 6
FWCI
8.60
Type
journal article
Language
en
Open access
Locations
  • Molecular Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion)
Funders
  • National Institutes of Health (F31 CA189744, T32 CA115299, T32 GM008076)
  • National Cancer Institute (R01 CA174761, R21 CA194973)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
ATP citrate lyase, acetyl-CoA, histone acetylation, homologous recombination, DNA damage response, DNA double-strand breaks, 53BP1, BRCA1, ATM, Akt, protein phosphorylation, PARP inhibition, genomic instability, DNA repair pathway choice
MeSH terms
Poly(ADP-ribose) Polymerase Inhibitors, Tumor Suppressor p53-Binding Protein 1, A549 Cells, Acetyl Coenzyme A, Acetylation, Animals, ATP Citrate (pro-S)-Lyase, Cell Nucleus, Female, Glucose, HeLa Cells, Histones, Humans, Melanoma, Experimental, Mice, Inbred C57BL, Phosphorylation, Protein Binding, Protein Processing, Post-Translational, Serine, Time Factors, Transfection, BRCA1 Protein, RNA Interference, Genomic Instability, HCT116 Cells, DNA Breaks, Double-Stranded, G2 Phase Cell Cycle Checkpoints, Recombinational DNA Repair, S Phase Cell Cycle Checkpoints

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