Structure-guided inhibition of the cancer DNA-mutating enzyme APOBEC3A

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dc.citation.volume14
dc.contributor.authorHarjes S
dc.contributor.authorKurup HM
dc.contributor.authorRieffer AE
dc.contributor.authorBayarjargal M
dc.contributor.authorFilichetva J
dc.contributor.authorSu Y
dc.contributor.authorHale TK
dc.contributor.authorFilichev VV
dc.contributor.authorHarjes E
dc.contributor.authorHarris RS
dc.contributor.authorJameson GB
dc.date.accessioned2024-10-02T19:51:34Z
dc.date.available2024-10-02T19:51:34Z
dc.date.issued2023-10-11
dc.description.abstractThe normally antiviral enzyme APOBEC3A 1-4 is an endogenous mutagen in many different human cancers 5-7 , where it becomes hijacked to fuel tumor evolvability. APOBEC3A’s single-stranded DNA C-to-U editing activity 1-8 results in multiple mutagenic outcomes including signature single-base substitution mutations (isolated and clustered), DNA breakage, and larger-scale chromosomal aberrations 5-7 . Transgenic expression in mice demonstrates its tumorigenic potential. APOBEC3A inhibitors may therefore comprise a novel class of anti-cancer agents that work by blocking mutagenesis, preventing tumor evolvability, and lessening detrimental outcomes such as drug resistance and metastasis. Here we reveal the structural basis of competitive inhibition of wildtype APOBEC3A by hairpin DNA bearing 2’-deoxy-5-fluorozebularine in place of the cytidine in the TC recognition motif that is part of a three-nucleotide loop. The nuclease-resistant phosphorothioated derivatives of these inhibitors maintain nanomolar in vitro potency against APOBEC3A, localize to the cell nucleus, and block APOBEC3A activity in human cells. These results combine to suggest roles for these inhibitors to study A3A activity in living cells, potentially as conjuvants, leading toward next-generation, combinatorial anti-mutator and anti-cancer therapies.
dc.description.confidentialfalse
dc.edition.edition2023
dc.identifier.citationJameson G, Harjes S, Kurup H, Rieffer A, Bayarjargal M, Filichetva J, Su Y, Hale T, Filichev V, Harjes E, Harris R. (2023). Structure-guided inhibition of the cancer DNA-mutating enzyme APOBEC3A. Nature Communications. 14.
dc.identifier.doi10.21203/rs.3.rs-2598101/v1
dc.identifier.eissn2041-1723
dc.identifier.elements-typejournal-article
dc.identifier.number6382
dc.identifier.urihttps://mro.massey.ac.nz/handle/10179/71573
dc.languageEnglish
dc.publisherSpringer Nature Limited
dc.publisher.urihttps://www.nature.com/articles/s41467-023-42174-w
dc.relation.isPartOfNature Communications
dc.rights(c) 2023 The Author/s
dc.rightsCC BY 4.0
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCancer
dc.subjectDNA
dc.subjectEnzyme mechanisms
dc.subjectX-Ray crystallography
dc.titleStructure-guided inhibition of the cancer DNA-mutating enzyme APOBEC3A
dc.typeJournal article
pubs.elements-id461377
pubs.organisational-groupOther
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