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

Simple item page
dc.citation.issue1
dc.citation.volume14
dc.contributor.authorHarjes S
dc.contributor.authorKurup HM
dc.contributor.authorRieffer AE
dc.contributor.authorBayarjargal M
dc.contributor.authorFilitcheva 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.coverage.spatialEngland
dc.date.accessioned2024-08-13T20:26:56Z
dc.date.available2024-08-13T20:26:56Z
dc.date.issued2023-10-11
dc.description.abstractThe normally antiviral enzyme APOBEC3A is an endogenous mutagen in human cancer. Its single-stranded DNA C-to-U editing activity results in multiple mutagenic outcomes including signature single-base substitution mutations (isolated and clustered), DNA breakage, and larger-scale chromosomal aberrations. APOBEC3A inhibitors may therefore comprise a unique class of anti-cancer agents that work by blocking mutagenesis, slowing tumor evolvability, and preventing 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 substrate motif that is part of a 3-nucleotide loop. In addition, the structural basis of APOBEC3A's preference for YTCD motifs (Y = T, C; D = A, G, T) is explained. The nuclease-resistant phosphorothioated derivatives of these inhibitors have nanomolar potency in vitro and block APOBEC3A activity in human cells. These inhibitors may be useful probes for studying APOBEC3A activity in cellular systems and leading toward, potentially as conjuvants, next-generation, combinatorial anti-mutator and anti-cancer therapies.
dc.description.confidentialfalse
dc.format.pagination6382-
dc.identifier.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/37821454
dc.identifier.citationHarjes S, Kurup HM, Rieffer AE, Bayarjargal M, Filitcheva J, Su Y, Hale TK, Filichev VV, Harjes E, Harris RS, Jameson GB. (2023). Structure-guided inhibition of the cancer DNA-mutating enzyme APOBEC3A.. Nat Commun. 14. 1. (pp. 6382-).
dc.identifier.doi10.1038/s41467-023-42174-w
dc.identifier.eissn2041-1723
dc.identifier.elements-typejournal-article
dc.identifier.issn2041-1723
dc.identifier.number6382
dc.identifier.pii10.1038/s41467-023-42174-w
dc.identifier.urihttps://mro.massey.ac.nz/handle/10179/71270
dc.languageeng
dc.publisherSpringer Nature Limited
dc.publisher.urihttps://www.nature.com/articles/s41467-023-42174-w
dc.relation.isPartOfNat Commun
dc.rights(c) 2023 The Author/s
dc.rightsCC BY 4.0
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectHumans
dc.subjectProteins
dc.subjectMutagenesis
dc.subjectNeoplasms
dc.subjectDNA
dc.subjectCytidine Deaminase
dc.titleStructure-guided inhibition of the cancer DNA-mutating enzyme APOBEC3A.
dc.typeJournal article
massey.identifier.uri-duplicatehttps://hdl.handle.net/10179/70313
pubs.elements-id480937
pubs.organisational-groupCollege of Health
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