Two redundant ubiquitin-dependent pathways of BRCA1 localization to DNA damage sites
Bibliographic record
Abstract
Abstract The tumor suppressor BRCA1 accumulates at sites of DNA damage in a ubiquitin-dependent manner. In this work, we revisit the role of the ubiquitin-binding protein RAP80 in BRCA1 recruitment to damaged chromatin. We found that RAP80, or the phosphopeptide-binding residues in the BRCA1 BRCT domains, act redundantly with the BRCA1 RING domain to promote BRCA1 recruitment to DNA double-strand break sites. We show that that RNF8 E3 ubiquitin ligase acts upstream of both the RAP80- and RING-dependent activities whereas RNF168 acts uniquely upstream of the RING domain. The function of the RING domain in BRCA1 recruitment is not solely linked to its role in mediating an interaction with BARD1 since RING mutations that do not impact BARD1 interaction, such as the E2-binding deficient Ile26Ala (I26A) mutation, produce a BRCA1 protein unable to accumulate at DNA damage sites in the absence of RAP80. Cells that combine the BRCA1 I26A mutation and mutations that disable the RAP80-BRCA1 interaction are deficient in RAD51 filament formation and are hypersensitive to poly (ADP-ribose) polymerase inhibition. Our results suggest that in the absence of RAP80, the BRCA1 E3 ligase activity is necessary for the recognition of unmethylated histone H4 Lys20 and histone H2A Lys13/Lys15 ubiquitylation by BARD1 although we cannot rule out the possibility that the RING- E2 complex itself may facilitate ubiquitylated nucleosome recognition in other ways. Finally, given that tumors expressing RING-less BRCA1 isoforms readily acquire resistance to therapy, this work suggests that targeting RAP80, or its interaction with BRCA1, could represent a novel strategy for restoring sensitivity of such tumors to DNA damaging agents.
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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 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
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".