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J. Mol. Biol. · Vol 436 · Issue 8 · 2026doi:10.1016/jmb.2026.04.138Received 12 Jan · Revised 9 Mar · Accepted 28 Mar 2026 · Open AccessRAD51–BRCA2 coupling stabilises replicationforks under oncogene-induced stressA. Thornton, M. Delgado, P. Ramaswamy, J. O'Brien, L. Hartmann, H. Tanaka¹Stanford University · ²MIT · ³Chan Zuckerberg Biohub · ⁴RIKEN · *[email protected]AbstractReplication stress is a hallmark of oncogene-driven tumorigenesis, yet how RAD51 and BRCA2 stabilise stalledforks in primary human cells remains incompletely resolved. We apply longitudinal single-cell imaging (n = 4,812cells, 23 donors) to quantify fork restart kinetics under hydroxyurea challenge, and show RAD51 residence timescales with BRCA2 occupancy (R² = 0.84, p < 0.001), a coupling disrupted in BRCA2-L2510P carriers.Keywords: replication stress · homologous recombination · RAD51 · BRCA2 · single-cell imaging1. IntroductionThe integrity of replication forks under oncogenic stressis a central fulcrum of genome stability [1,2]. RAD51nucleofilament assembly is rate-limiting for protection[3], and its loading by BRCA2 is a canonical tumour-suppressive axis [5,6]. Prior bulk assays gave inconsistentRAD51:BRCA2 ratios for fork stability, motivating thesingle-cell, single-molecule approach developed here.2. ResultsWe established a longitudinal imaging pipeline in CD34⁺progenitors, tracking endogenous RAD51-mEGFP and BRCA2-mCherry across 72 h of hydroxyurea exposure (Fig. 1).Single-molecule photobleaching confirmed 1:1 labelling;fork-restart frequency correlated with mean RAD51residence time (τ_res = 18.3 ± 2.1 s, Fig. 2).250150100755037RAD51BRCA2γH2AXα-tubulinCtrlWTWT+HUKOL2510PFig. 1. Immunoblot of iPOND fork complexes; co-enrichmentof RAD51/BRCA2 is lost in L2510P carriers (lane 5).2.1 Single-molecule trackingImaging used a Nikon Ti2 with a 60× 1.49 NA TIRFobjective at 50 ms exposure, 10 Hz, over 600 s per field.Trajectories were linked in TrackMate v7.11 and filteredfor SNR > 4. Restart latencies were bimodal: a fastpopulation (τ₁ = 41 ± 6 s) comprised 68% of events, theslow class enriched in monoallelic BRCA2 carriers.2.2 Fork-complex compositioniPOND immunoblots showed stoichiometric co-enrichment ofRAD51 and BRCA2 in wild-type cells (ratio 1.07 ± 0.14),falling to 0.31 ± 0.08 in L2510P (p < 0.001). This losstracked with accelerated fork degradation and elevatedγH2AX, indicating compromised fork protection. DNA combingconfirmed reduced fork speed and symmetry in carriers.3. MethodsCD34⁺ cells from three donors (Stanford IRB #2026-0418)were cultured in StemSpan SFEM II with SCF, FLT3L and TPO.Hydroxyurea was applied at 2 mM for the durations shown.Foci were segmented with Cellpose and quantified pernucleus; comparisons used two-way ANOVA with Bonferronicorrection. The fork-restart rate constant was derived as:krest=[BRCA2] · τK_d + [BRCA2](1)20406080102540557085100Time after HU (min)RAD51 foci / nucleusControl (n=23)L2510P (n=18)***Fig. 2. Focus-resolution kinetics; L2510P shows acceleratedloss (p < 0.001, two-way ANOVA, error bars = SEM).Confocal imaging of nuclear foci revealed pronouncedspatial co-localisation of RAD51 and γH2AX at stalledforks (Fig. 3; Pearson r = 0.78, n = 412 fields), largelyabsent in cells lacking functional BRCA2.5µmDAPI5µmRAD515µmγH2AX5µmMergeFig. 3. Confocal RAD51/γH2AX foci; scale bar 5 µm.Table 1. Summary statistics (mean ± SD).GenotypenfociτpWT239.141–Het217.473.02L2510P185.3112<.001Data: zenodo.org/record/10918842References[1] Zeman MK, Cimprich KA.Causes & consequences of replication stress. Nat Cell Biol (2014).[2] Moldovan GL, Pfander B, et al.PCNA, the maestro of the replication fork. Cell (2007).[3] Taglialatela A, Alvarez S, et al.Fork stability in BRCA1/2-deficient cells. Mol Cell (2017).[4] Schlacher K, Christ N, et al.BRCA2 blocks stalled fork degradation. Cell (2011).[5] Lomonosov M, Anand S, et al.Stabilization of stalled forks by BRCA2. Genes Dev (2003).[6] Mijic S, Zellweger R, et al.Fork reversal in BRCA2-defective cells. Nat Commun (2017).AI-generated textAI-generated textImage manipulationImage manipulationImage duplicationImage duplicationAI-generated imagesAI-generated imagesGraph & chart duplicationGraph & chart duplicationStatistical consistencyStatistical consistencyFigure–legend matchFigure–legend matchDOI & metadataDOI & metadataImage plagiarismImage plagiarismRetracted referencesRetracted referencesHallucinated referencesHallucinated referencesData availabilityData availabilityAuthor identityAuthor identityPaper-mill signalsPaper-mill signalsCitation patternsCitation patternsResearch ethicsResearch ethicsMethods & rigorMethods & rigorNovelty & contributionNovelty & contributionPeer-review analysisPeer-review analysisReproducibilityReproducibilityReplicabilityReplicabilityDOI & metadataMethods & rigorStatistical consistencyClaim–citation consistencyImage manipulationRetracted references
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ReferencesAll 58Retracted 1Hallucinated 1Unsupported 3
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    Zhang et al., 2019

    Retraction Watch, 2022

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