Exploring APOBEC3 domain structure: impact on recognition of DNA damage
Bibliographic record
Abstract
Activation-induced deoxycytidine deaminase (AID) and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3 (APOBEC3, or A3) enzymes are a family of deoxycytidine (dC) deaminases involved in somatic hypermutation (SHM), antibody class switch recombination, and antiviral responses. These enzymes share similar structural features in their single active deoxycytidine deaminase (CD) domain, but some family members (A3B/DE/F/G) possess an additional second regulatory CD domain also known as an N-terminal domain (Ntd). AID/A3s mutate the genome indiscriminately, and A3A, A3B, and A3H haplotype II have been associated with cancer development. Thus, to date the paradigm has been that AID/A3s are pro-tumour factors because they transform healthy DNA into damaged and mutated DNA. However, I observed that the activity of A3A (single domain) and A3B (double domain) is increased if their substrate DNA contains environmentally damaged nucleotides such as 8-Oxo-2’-deoxyguanosine (8oxoG) directly adjacent to the dC (in the -2 or -1 nucleotide position). When exposed to substrates containing damaged nucleotides in positions further downstream, further upstream, or containing a greater concentration of damaged bases, A3A failed to demonstrate an activity increase relative to undamaged and -1 position 8oxoG control substrates whereas A3B exhibited significantly increased activity for all distally damaged substrates compared to controls. I propose that the regulatory Ntd of A3B is a key structural component that accounts for binding distally damaged DNA substrates. The notion that AID/A3s can target pre-damaged DNA in addition to non-damaged healthy DNA is a novel insight in the field; understanding the basis of this phenomenon from both the substrate sequence and enzyme structure point of view would advance our basic knowledge and permit exploration of targeting AID/A3 enzymes in cancer.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".