Interstrand Cross-Link Induction by UV Radiation in Bromodeoxyuridine-Substituted DNA: Dependence on DNA Conformation
Bibliographic record
Abstract
DNA interstrand cross-links (ICL) can be induced both by natural products (e.g., psoralens with UVA) and by chemical agents, some of which are used in chemotherapy (e.g., Carboplatin and mitomycin C). Here, we report the formation of ICL by UV radiation in brominated DNA, but only for very specific conformations. The quantum yields for strand break and cross-link formation depend on the wavelength with a maximum near 280 nm. It is known that the photosensitization of DNA by bromodeoxyuridine (BrdUrd) results mainly from the electron affinity of bromine, leading to the irreversible formation of 2'-deoxyuridin-5-yl radicals (dUrd*) upon the addition of an electron from an adjacent adenosine. It is well documented that the photolytic loss of the bromine atom is greatly suppressed in single-stranded DNA versus that in double-stranded DNA. To study this behavior, we have used two models of BrdUrd-mediated sensitization: one consists of a DNA duplex containing a bulge, formed by five mismatched bases, including the BrdUrd, and the other consists of completely duplex DNA. UV irradiation induces much higher levels of single-strand breaks (ssb) in the completely duplex DNA at the BrdUrd site compared to the DNA with a bulge. However, in completely duplex DNA, ssb appear only in the brominated strand, whereas in the bulged duplex DNA, ssb occur on both strands. Most importantly, we also observe formation of interstrand cross-links in bulged duplex DNA in the BrdUrd region. Thus, we propose that UV irradiation of cells containing BrdUrd incorporated randomly into duplex DNA will create many ssb, whereas BrdUrd present in DNA bulges or open regions in double-stranded DNA (transcription bubbles, replication forks) will lead to potentially lethal damage in both strands in the form of ICL. These findings may help explain the potent clinical antiviral activity of IdUrd and BrdUrd (e.g., IdUrd is used to treat eye infections caused by the herpes virus) and suggest that ICL formation may be a very specific probe for identifying single-stranded regions in the DNA of living cells. In addition, this model system provides an excellent means of introducing ICL for studies on their repair and biological consequences.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".