Replication catastrophe induced by cyclic hypoxia leads to increased APOBEC3B activity

Abstract Tumor heterogeneity includes variable and fluctuating oxygen concentrations, which result in the accumulation of hypoxic regions in most solid tumors. Tumor hypoxia leads to increased therapy resistance and has been linked to genomic instability. Here, we tested the hypothesis that exposure...

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Veröffentlicht in:Nucleic acids research Jg. 49; H. 13; S. 7492 - 7506
Hauptverfasser: Bader, Samuel B, Ma, Tiffany S, Simpson, Charlotte J, Liang, Jiachen, Maezono, Sakura Eri B, Olcina, Monica M, Buffa, Francesca M, Hammond, Ester M
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England Oxford University Press 21.07.2021
Schlagworte:
APOBEC Deaminases - metabolism
Cell Hypoxia
Cell Line, Tumor
Cytidine Deaminase - metabolism
Deamination
DNA Replication
Genome Integrity, Repair and
Humans
Hydroxyurea - toxicity
Minor Histocompatibility Antigens - metabolism
Neoplasms - enzymology
Stress, Physiological - genetics
ISSN:0305-1048, 1362-4962, 1362-4962
Online-Zugang:Volltext
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Zusammenfassung:Abstract Tumor heterogeneity includes variable and fluctuating oxygen concentrations, which result in the accumulation of hypoxic regions in most solid tumors. Tumor hypoxia leads to increased therapy resistance and has been linked to genomic instability. Here, we tested the hypothesis that exposure to levels of hypoxia that cause replication stress could increase APOBEC activity and the accumulation of APOBEC-mediated mutations. APOBEC-dependent mutational signatures have been well-characterized, although the physiological conditions which underpin them have not been described. We demonstrate that fluctuating/cyclic hypoxic conditions which lead to replication catastrophe induce the expression and activity of APOBEC3B. In contrast, stable/chronic hypoxic conditions which induce replication stress in the absence of DNA damage are not sufficient to induce APOBEC3B. Most importantly, the number of APOBEC-mediated mutations in patient tumors correlated with a hypoxia signature. Together, our data support the conclusion that hypoxia-induced replication catastrophe drives genomic instability in tumors, specifically through increasing the activity of APOBEC3B.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:0305-1048
1362-4962
1362-4962
DOI:10.1093/nar/gkab551