APOBEC1 cytosine deaminase activity on single-stranded DNA is suppressed by replication protein A

Wong, Lai Hong; Vizeacoumar, Frederick S.; Chelico, Linda

doi:10.1093/nar/gkaa1201

Cited by 19 publications

(27 citation statements)

References 96 publications

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“…It is well established that non-B DNA structures cause replication stalling and require special systems aiding to replicate these regions 34 . This could lead to higher recruitment of replication protein A (RPA), which binds to ssDNA and is known to counteract APOBEC deamination 35,36 . An alternative or an additional explanation could be recruiting for replicating of non-B DNA regions the specific DNA polymerase called Primase-Polymerase (PrimPol).…”

Section: Discussionmentioning

confidence: 99%

APOBEC mutagenesis is low in most types of non-B DNA structures, unlike other types of cancer mutagenesis

Ponomarev

Fatykhov

Nazarov

et al. 2021

Preprint

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While somatic mutations are known to be enriched in genome regions with non-canonical DNA secondary structure, the impact of particular mutagens still needs to be elucidated. Here, we demonstrate that in human cancers, the APOBEC mutagenesis is not enriched in direct repeats, mirror repeats, short tandem repeats, and G-quadruplexes, and even decreased below its level in B-DNA for cancer samples with very high APOBEC activity. In contrast, we observe that the APOBEC-induced mutational density is positively associated with APOBEC activity in inverted repeats (cruciform structures), where the impact of cytosine at the 3'-end of the hairpin loop is substantial. Surprisingly, the APOBEC-signature mutation density per TC motif in the single-stranded DNA of a G-quadruplex (G4) is lower than in the four-stranded part of G4 and in B-DNA. The APOBEC mutagenesis, as well as the UV-mutagenesis in melanoma samples are absent in Z-DNA regions, due to depletion of their mutational signature motifs.

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Section: Discussionmentioning

confidence: 99%

APOBEC mutagenesis is low in most types of non-B DNA structures, unlike other types of cancer mutagenesis

Ponomarev

Fatykhov

Nazarov

et al. 2021

Preprint

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“…Further exploration is necessary to find efficient and specific Ades in addition to those tested in this study. In addition to virus-derived Ades, it has been reported that single-stranded binding proteins, small-molecule inhibitors and chemically modified oligonucleotides can suppress the cytosine deaminase activity of APOBEC deaminases 60 – 65 . These potential antagonists of deaminases merit further exploration to develop new inhibitors of CBEs in the future.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of base editors with anti-deaminases derived from viruses

et al. 2022

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Cytosine base editors (CBEs), combining cytidine deaminases with the Cas9 nickase (nCas9), enable targeted C-to-T conversions in genomic DNA and are powerful genome-editing tools used in biotechnology and medicine. However, the overexpression of cytidine deaminases in vivo leads to unexpected potential safety risks, such as Cas9-independent off-target effects. This risk makes the development of deaminase off switches for modulating CBE activity an urgent need. Here, we report the repurpose of four virus-derived anti-deaminases (Ades) that efficiently inhibit APOBEC3 deaminase-CBEs. We demonstrate that they antagonize CBEs by inhibiting the APOBEC3 catalytic domain, relocating the deaminases to the extranuclear region or degrading the whole CBE complex. By rationally engineering the deaminase domain, other frequently used base editors, such as CGBE, A&CBE, A&CGBE, rA1-CBE and ABE8e, can be moderately inhibited by Ades, expanding the scope of their applications. As a proof of concept, the Ades in this study dramatically decrease both Cas9-dependent and Cas9-independent off-target effects of CBEs better than traditional anti-CRISPRs (Acrs). Finally, we report the creation of a cell type-specific CBE-ON switch based on a microRNA-responsive Ade vector, showing its practicality. In summary, these natural deaminase-specific Ades are tools that can be used to regulate the genome-engineering functions of BEs.

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“…It is well established that non-B DNA structures cause replication stalling and require special systems aiding to replicate these regions ( Wang and Vasquez, 2017 ). This could lead to higher recruitment of replication protein A (RPA), which binds to ssDNA and is known to counteract APOBEC deamination ( Brown et al., 2021 ; Wong et al., 2021 ). An alternative or an additional explanation could be recruiting for the replicating of non-B DNA regions the specific DNA polymerase called Primase-Polymerase (PrimPol).…”

Section: Discussionmentioning

confidence: 99%