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Open research questions in DNA Repair Mechanisms

60 unresolved questions extracted from the limitations and future-work sections of 247 DNA Repair Mechanisms papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • 1d), it remains to be tested whether PCNA1 can become lim- iting. In this study, we have addressed the open question of how asynchro- nous nuclear multiplication arises in P.

    Competitive resource allocation drives asynchronous and rapid nuclear multiplication in the malaria parasite · 2026 · DOI

  • DNA mismatch repair (MMR) safeguards genome stability by correcting replication errors, yet how its components coordinate as an efficient pathway in living cells remains unclear.

    Replication-coupled search positions MutH for strand incision in DNA mismatch repair · 2026 · DOI

  • BRCA2, a tumor suppressor vital for homologous recombination (HR), also contributes to R-loop regulation, though the underlying mechanisms remain poorly understood.

    HELZ-BRCA2 complex resolves R-loops to drive transcription-coupled homologous recombination · 2026 · DOI

  • Paradoxically, cells inactivate canonical DNA repair mechanisms during chromosome segregation in favor of alternative pathways that depend on TOPBP1 and CIP2A, but how they function is still poorly defined.

    DDIAS is a single-stranded DNA-binding effector of the TOPBP1-CIP2A complex in mitosis · 2026 · DOI

  • Background Chemoradiotherapy (CRT) remains a cornerstone of treatment for multiple solid malignancies; however, durable disease control is frequently limited by the emergence of resistance.

    Convergent adaptive architectures linking chemoresistance and radioresistance in chemoradiotherapy: a systems-level perspective · 2026 · DOI

  • Whether p53 acts merely as a parallel stress pathway, or actively reshapes how an activated JAK/STAT1 response is temporally decoded and functionally routed, remains unclear.

    How p53 stress memory could redirect JAK/STAT1 antiviral signalling: a model-based prediction. · 2026 · DOI

  • The endonuclease (EN) domain of the LINE-1 ORF2 protein (ORF2p) generates DNA strand breaks, yet its role in shaping downstream chromatin and transcriptional responses remains poorly defined.

    LINE-1 transposon derived DNA lesions reshape the chromatin landscape to promote genome instability · 2026 · DOI

  • However, whether DNA-damage can induce mechanical changes that regulate downstream events such as YAP localization and that in turn feeds back onto DDR activation, remains unknown.

    Mechanics-dependent Global Nuclear Eviction and Site-Specific Recruitment of YAP Regulates DNA Damage Responses · 2026 · DOI

  • The chromatin architectural proteins cohesin and CTCF are known critical organizers of TADs, but the mechanisms of TAD establishment and maintenance, including their accurate duplication during genome replication, are not well characterized.

    Re-establishment of TAD boundary organization during DNA replication · 2026 · DOI

  • In budding yeast, the meiotic chromosome axis, built on Rec8-containing cohesin together with Red1 and Hop1, acts as a central platform regulating meiotic recombination from programmed DNA double-strand break (DSB) formation to checkpoint signaling and chromosome segregation, yet how cohesin recruits axis proteins remains unclear.

    Cohesin-axis interaction via a conserved Red1 motif promotes domain-specific DSB formation and Mek1 activation · 2026 · DOI

  • Further details of the SFBF model remain to be elucidated. 3 It remains unclear why cancers with CDK12 loss and CCNE1 amplification exhibit large tandem duplications centered at replication origins. 20,37 In contrast to larger (> 100 kb) TDs where our data supports the SFBF model, smaller duplications do not show origin enrichment (Figure S3) and their APOBEC strand patterns are inconclusive.

    Replication fork directionality reveals how structural variants arise under replication stress · 2026 · DOI

  • Topoisomerase III (TOP3) can also resolve catenanes, but its direct role during DNA replication, substrate specificity, and relevant binding partners remain unclear.

    Topoisomerase IIIα resolves inter- and intra-molecular intertwines during DNA replication · 2026 · DOI

  • The upstream regulatory programs that support the biomass production needed for DNA replication, particularly in the accelerated growth setting of cancer, remain incompletely defined.

    ATF4 coordinates amino acid and nucleotide synthesis with selective protein translation to ensure proper DNA replication timing in leukemia cells · 2026 · DOI

  • In mammals, the axis is assembled from the coiled-coil elements SYCP2 and SYCP3 that come together with the HORMA-domain proteins HORMAD1 and HORMAD2, but how these components associate into a coherent structural unit remains incompletely understood.

    Assembly principles of a SYCP2-HORMAD1-HORMAD2 mammalian meiotic axis complex · 2026 · DOI

  • In mice, the mini-chromosome maintenance family protein, MCM8, has been proposed to function in meiotic recombination and its loss leads to infertility, but the underlying mechanisms are poorly understood.

    Critical roles of MCM8 in meiotic recombination during mouse spermatogenesis · 2026 · DOI

  • Identifying DNA replication origins in human and other metazoan genomes has been challenging, as highlighted by the fact that various methods for mapping them have produced conflicting results.

    Improved short nascent strand sequencing (iSNS-seq) enhances DNA replication origin detection and reduces non-origin biases · 2026 · DOI

  • Replication fork reversal occurs in response to the ICL-inducing drug, MMC, but how replication fork reversal promotes repair of ICLs is poorly understood.

    RAD54L promotes nascent DNA degradation and radial chromosome formation in FANC-deficient cells · 2026 · DOI

  • Homologous recombination (HR) between sister chromatids is the dominant outcome of replication-associated DNA repair, yet the lesions that initiate spontaneous mitotic crossovers remain poorly defined.

    Lesions initiating spontaneous mitotic crossover are minimally subject to non-homologous end joining · 2026 · DOI

  • In mammals, PRDM9-dependent H3K4me3 and H3K36me3 define recombination hotspots, but how these epigenetic characteristics determine the physiological DSB formation remains unknown.

    Dual histone methylation reader ZCWPW2 links histone methylation to initiation of meiotic recombination · 2026 · DOI

  • 53BP1 nuclear bodies are dynamic structures with properties resembling biomolecular condensates, but the molecular determinants that govern 53BP1 higher-order assembly at DNA double-strand breaks (DSBs) remain to be established.

    Phosphatidylinositol 3-phosphate promotes 53BP1 condensate-like assembly at DNA double-strand breaks · 2026 · DOI

  • The enzyme apurinic/apyrimidinic endonuclease-1 (Apex1) is essential for base-excision repair, but its role in protecting the brain from age-related deterioration remains unclear.

    Caloric restriction decelerates premature aging and cognitive decline in mice with deficient DNA repair · 2026 · DOI

  • Dysregulation of Speckle-type POZ protein (SPOP) and cargo receptor p62/SQSTM1 impairs homologous recombination (HR)-mediated DNA repair by destabilizing RAD51 and FLNA, yet their mechanistic interplay in genomic stability and oncogenesis remains unclear.

    SPOP-mediated nuclear ubiquitination degradation of p62/SQSTM1 contributes to HR repair · 2026 · DOI

  • A broad suite of HTS-based technologies has been developed to study DNA metabolism. This review has highlighted those designed to monitor DNA replication and DNA damage repair, outlining their principles, technical features, and applications across physiological development, pathological contexts, and emerging therapeutic strategies. As these HTS- based technologies continue to evolve, several trajectories are shaping their future impact. Resolution is steadily advancing toward the single-cell and single-molecule scale, enabling detection of replication and repair heterogeneity that bulk assays obscure. Multi- omics integration is becoming routine, linking replication and repair readouts to the epigenome, transcriptome, pro- teome, and 3D genome organization. Improvements in quantitative precision and sensitivity are allowing increas- ingly accurate assessments of fork kinetics, damage occur- rence, and repair efficiencies. In addition, combining spatially resolved transcriptomics, epigenomics, and prote- omics with high-resolution profiling of DNA metabolism will allow DNA replication and damage repair processes to be mapped in situ, revealing how they vary across tissue niches and evolve over time. Such approaches promise to uncover interactions, and clonal trajectories, microenvironment In parallel, spatially localized genomic perturbations. enhanced compatibility with low-input samples is enabling applications to early embryos, rare tumor sub-populations, and clinically limited biopsies. Together, these methodolog- ical advances will deepen our understanding of genome stability maintenance mechanisms and accelerate the translation of and DNA- metabolism research into clinical practice. genome-editing therapies Acknowledgments: We thank all members of the Liu labo- ratory for their insightful comments and constructive feed- back. We also apologize to colleagues whose valuable work could not be cited due to space constraints. Research ethics: IRB approval is not applicable to this work. Informed consent: Not applicable. Author contributions: All authors have accepted re- sponsibility for the entire content of this manuscript and approved its submission. Jingzhi Luo, Conceptualization, Writing original draft, Writing review & editing, Visualiza- tion. Fanyu Zhao, Writing review & editing, Visualization. Shuyan Lin, Writing review& editing, Visualization. Yang Liu, Conceptualization, writing review & editing, Supervi- sion, Funding acquisition. Use of Large Language Models, AI and Machine Learning Tools: None declared. Conflict of interest: The authors state no conflict of interest. Research funding: This work was supported by the NSFC grant (32522018 to Y.L.) and the Clinical Medicine Plus X-Young Scholars Project, Peking University, the Funda- mental Research Funds for the Central Universities. Data availability: Not applicable.

    Decoding DNA metabolism and its clinical relevance through the lens of high-throughput sequencing assays · 2026 · DOI

  • The mechanism underlying selective ATR dependence in NBS1-deficient cells during G2 phase versus S-phase requires further mechanistic elucidation beyond the current Rad51 and chromosomal aberration…

    Generation of NBS1 knockout in Chinese hamster cells revealed ATR role for radiation and etoposide induced DNA damage in absence of NBS1 proteins · 2026 · DOI

  • Future studies using synchronized cell populations would clarify this limitation and potentially reveal heightened sensitivity to bleomycin, UV-C and hydroxyurea in NBS1 mutant…

    Generation of NBS1 knockout in Chinese hamster cells revealed ATR role for radiation and etoposide induced DNA damage in absence of NBS1 proteins · 2026 · DOI

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60 open questions have been extracted from the limitations and future-work passages of 247 DNA Repair Mechanisms papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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