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PubMed2025

NuRD chromatin remodeling is required to repair exogenous DSBs in the Caenorhabditis elegans germline.

Organisms rely on coordinated networks of DNA repair pathways to protect genomes against toxic double-strand breaks (DSBs), particularly in germ cells. All repair mechanisms must successfully negotiate the local chromatin environment in order to access DNA. For example, nucleosomes can be repositioned by the highly conserved Nucleosome Remodeling and Deacetylase (NuRD) complex. In Caenorhabditis elegans, NuRD functions in the germline to repair DSBs - the loss of NuRD's ATPase subunit, LET-418/CHD4, prevents DSB resolution and therefore reduces fertility. In this study, we challenge germlines with exogenous DNA damage to better understand NuRD's role in repairing DSBs. We find that let-418 mutants are sensitive to cisplatin and hydroxyurea: exposure to either mutagen impedes DSB repair, generates aneuploid oocytes, and reduces fertility and embryonic survival. These defects resemble those seen when the Fanconi anemia (FA) DNA repair pathway is compromised, and we find that LET-418's activity is epistatic to that of the FA component FCD-2/FANCD2. We propose a model in which NuRD is recruited to the site of DNA lesions to remodel chromatin and allow access for FA pathway components. Together, these results implicate NuRD in the repair of both endogenous DSBs and exogenous DNA lesions to preserve genome integrity in developing germ cells.

DNA repair↗

PubMed2026

The role of CHAMP1 in chromatin-mediated DNA damage repair.

Defects in the replication stress response are major drivers of cancer development and present key targetable vulnerabilities that can be exploited for anti-cancer therapy. Recent studies have identified CHAMP1 as a novel DNA damage repair factor with roles in double-strand break repair and the replication stress response. Mutations in CHAMP1 are associated with the neurodevelopmental disorder CHAMP1 Syndrome. More recently, children with CHAMP1 Syndrome have developed leukemia, suggesting that CHAMP1 mutations are a potential cancer risk factor. CHAMP1 is part of two DNA damage repair complexes: CHAMP1-POGZ-REV7 (Complex I) and CHAMP1-POGZ-HP1α (Complex II). Complex I promotes homologous recombination by removing the Shieldin complex from the ends of double strand breaks and allowing DSB end resection to occur. Complex II enriches heterochromatin content through the recruitment of the methyltransferase SETDB1 to DNA damage sites. Increased heterochromatin at stalled forks is associated with proper fork stability and restart, demonstrating the importance of CHAMP1 in maintaining genomic integrity. Loss of CHAMP1 leads to increased sensitivity to DNA damaging agents and increased dependence on other DNA damage repair pathways, such as the DNA damage checkpoint and the Fanconi Anemia pathway. CHAMP1 is overexpressed in breast and ovarian cancer cells with high levels of replication stress, providing a molecular mechanism for the tolerance of replication stress. These new findings on the relationship of CHAMP1 with well-established DNA damage repair pathways, suggest that targeting CHAMP1 could present a new synthetic lethality opportunity for cancer cells with high levels of replication stress.

CHAMP1↗

PubMed2021

Mechanism, cellular functions and cancer roles of polymerase-theta-mediated DNA end joining.

Cellular pathways that repair chromosomal double-strand breaks (DSBs) have pivotal roles in cell growth, development and cancer. These DSB repair pathways have been the target of intensive investigation, but one pathway - alternative end joining (a-EJ) - has long resisted elucidation. In this Review, we highlight recent progress in our understanding of a-EJ, especially the assignment of DNA polymerase theta (Polθ) as the predominant mediator of a-EJ in most eukaryotes, and discuss a potential molecular mechanism by which Polθ-mediated end joining (TMEJ) occurs. We address possible cellular functions of TMEJ in resolving DSBs that are refractory to repair by non-homologous end joining (NHEJ), DSBs generated following replication fork collapse and DSBs present owing to stalling of repair by homologous recombination. We also discuss how these context-dependent cellular roles explain how TMEJ can both protect against and cause genome instability, and the emerging potential of Polθ as a therapeutic target in cancer.

Animals↗

PubMed2026

CRISPR Screen Identifies HDAC3 as a Novel Radiosensitizing Target in Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is an aggressive malignancy, with most patients presenting with prognostically poor extensive-stage disease. Limited progress in standard care stresses the urgent need for novel therapies. Radiotherapy offers some survival benefit for selected patients with SCLC but could be enhanced with radiosensitizers. In this study, we identify HDAC3 as a novel radiosensitizing target in SCLC using a CRISPR knockout screen and demonstrate its efficacy and mechanism. SBC5 cells were transduced with a custom EpiDrug single-guide RNA library and treated with ionizing radiation (IR) to identify radiosensitizing genes. HDAC3 emerged as a candidate and was validated through genetic knockdown and pharmacologic inhibition (RGFP966) in multiple SCLC cell lines. Both approaches enhanced radiosensitivity, as shown by cell viability (dose modification factor10 = 1.14-1.69) and clonogenic assays (dose modification factor10 = 1.16-1.41). We assessed changes in chromatin accessibility by assay for transposase-accessible chromatin using sequencing and IR-induced DNA damage and repair using γH2AX foci detection, double-strand break (DSB) repair assays, and immunoblotting of repair proteins. HDAC3-deficient cells exhibited increased chromatin accessibility, greater IR-induced DSBs, and impaired repair capacity, resulting in persistent DNA damage. This repair defect sensitized cells to PARP inhibitors, for which combining RGFP966 with olaparib or talazoparib produced additive to synergistic effects. In SCLC xenograft models, HDAC3 knockdown or RGFP966, combined with IR, achieved significant tumor growth inhibition. Collectively, we identified HDAC3 as a novel radiosensitizing target in SCLC. Its functional loss increased the generation and persistence of IR-induced DNA DSBs, effectively sensitizing SCLC cell lines and xenografts to IR, providing a potential radiosensitization strategy to treat SCLC.

Humans↗

PubMed2024

The immediate-early protein 1 of human herpesvirus 6B interacts with NBS1 and inhibits ATM signaling.

Viral infection often trigger an ATM serine/threonine kinase (ATM)-dependent DNA damage response in host cells that suppresses viral replication. Viruses evolved different strategies to counteract this antiviral surveillance system. Here, we report that human herpesvirus 6B (HHV-6B) infection causes genomic instability by suppressing ATM signaling in host cells. Expression of immediate-early protein 1 (IE1) phenocopies this phenotype and blocks homology-directed double-strand break repair. Mechanistically, IE1 interacts with NBS1, and inhibits ATM signaling through two distinct domains. HHV-6B seems to efficiently inhibit ATM signaling as further depletion of either NBS1 or ATM do not significantly boost viral replication in infected cells. Interestingly, viral integration of HHV-6B into the host's telomeres is not strictly dependent on NBS1, challenging current models where integration occurs through homology-directed repair. Given that spontaneous IE1 expression has been detected in cells of subjects with inherited chromosomally-integrated form of HHV-6B (iciHHV-6B), a condition associated with several health conditions, our results raise the possibility of a link between genomic instability and the development of iciHHV-6-associated diseases.

Humans↗

PubMed2025

Rapid Generation of Recombinant Poxviruses Using CRISPR/Cas9 Gene Editing.

The low-frequency natural recombination that is detected in poxvirus-infected cells has long been used to genetically modify poxviruses. Such recombinant poxviruses have found many applications as vaccines for preventing infectious diseases and as experimental cancer therapeutics. Unfortunately, these methods are time consuming, can leave behind "scars" or selectable markers, and many months of work may be required to generate plaque-purified recombinants bearing multiple virus gene substitutions, deletions, and/or inserted transgenes. Over the last decade, several reports have described how CRISPR/Cas9 technologies can be used to better facilitate genetic manipulation of vaccinia virus (VACV). These protocols use Cas9/gRNA complexes to introduce double-stranded breaks into specific sites in virus genomic DNA either in vivo or in vitro. Recombination-repair reactions are then employed to repair the breaks using transfected DNAs encoding the required homologies and desired mutation(s). Here we describe a method where we combine CRISPR/Cas9 genome editing in vitro, followed by Leporipoxvirus-catalyzed repair and reactivation of the cut VACV DNA using repair fragments provided in trans. This method optimizes several steps in the preparation of the CRISPR/Cas9-cut VACV DNA and can be used to introduce mutations at multiple sites without requiring selectable markers. It also provides some guidance regarding how the position of the CRISPR/Cas9-cuts can affect co-conversion of flanking markers embedded in the repair fragment. The method allows researchers to quickly generate recombinant VACV bearing multiple genetic alterations and using only a single round of reactivation and plating.

CRISPR-Cas Systems↗

PubMed2026

The emerging landscape of polymerase θ in tumor pathogenesis and precision treatment.

DNA polymerase θ (Polθ) has emerged as a central yet paradoxical regulator of genome stability and tumor progression. Unlike conventional DNA repair factors, Polθ governs an error-prone double-strand break repair pathway-termed theta-mediated end joining (TMEJ)-which becomes essential for survival in homologous recombination (HR)-deficient cancers while simultaneously fueling genomic instability. This review presents a comprehensive and updated synthesis of Polθ's structural architecture, regulatory networks, and context-dependent functions across major malignancies, including ovarian, breast, lung, and colorectal cancers. We highlight recently uncovered mechanisms, such as the iron-FTH1/FTL-POLQ-RAD51 axis in platinum-resistant ovarian cancer, the differential POLQ regulation under methionine restriction in BRCA1-mutant breast cancer, and the identification of germline POLQ mutations defining a novel hereditary colorectal cancer subtype. Beyond DNA repair, we integrate emerging evidence linking Polθ to replication stress tolerance, base excision repair, and immune modulation via type I interferon activation and macrophage polarization. The review also provides a critical evaluation of current Polθ inhibitors-including ART558, RP-6685, novobiocin, and AB25583-focusing on their mechanisms, synthetic lethality profiles, and ability to overcome PARP inhibitor resistance. By bridging molecular mechanisms with tumor biology and therapeutic translation, this review offers a unique framework for understanding Polθ as both a prognostic biomarker and a precision oncology target, with implications for combination therapies involving radiotherapy, immunotherapy, and chemotherapy.

Cancer therapy↗

PubMed2026

Loss of Ku70 promotes mononucleate conidiation and homologous recombination in Phanerochaete chrysosporium.

Lignin is a major constituent of lignocellulose and the most abundant aromatic biopolymer on earth. It provides plants with rigidity and protection, but its recalcitrant nature also presents a significant barrier to lignocellulose valorization. The white-rot fungus Phanerochaete chrysosporium is among nature's most efficient lignin degraders, and its ligninolytic capabilities have been subjected to intensive investigations. Genome editing with precision is crucial for elucidating the in vivo mechanisms of its ligninolytic actions, but genetic manipulations of P. chrysosporium are often plagued by imprecision. This technical nuisance is driven primarily by canonical non-homologous end joining (c-NHEJ), a DNA repair system that requires little homology and depends on the binding of the Ku70/Ku80 heterodimer to double-strand break (DSB) ends. Loss of Ku70 or Ku80 abolishes c-NHEJ and significantly improves genome editing precision in many filamentous fungi, but it has yet to be examined and exploited in P. chrysosporium. Here, we constructed a homozygous ku70Δ mutant in a meiotic homokaryon of clear genetic background. Loss of Ku70 minimally impacts growth but significantly increases homologous recombination frequency from ~2% to ~66%, with ~32% of the latter being homozygous. Unexpectedly, loss of Ku70 also promotes mononucleate conidiation, which may facilitate isolation of homozygous mutants. Taken together, our work provides a valuable genetic tool to understand and exploit P. chrysosporium's remarkable ligninolytic capabilities.IMPORTANCEGenome editing with precision is essential to unraveling the intricacies of P. chrysosporium's exceptional ligninolytic capabilities, but the available tools are generally imprecise due to the dominance of non-homologous recombination, a problem that is further exacerbated by the discontinuation of Novozyme 234. We tackle these challenges by reestablishing protoplast-based transformation with Lywallzyme as an alternative. Importantly, we demonstrate that inactivation of c-NHEJ by deleting ku70 significantly increases gene knockout efficiency and report the unexpected involvement of c-NHEJ in regulating the number of nuclei during conidiation. Our work paves the way for future ventures into understanding ligninolysis in P. chrysosporium and building superior chassis for industrial applications.

Ku70↗

PubMed2026

Navigating the base excision repair pathway in chromatin-focus on oxidative DNA damage.

Chromatin environment influences all nuclear processes, including DNA repair. Conversely, DNA damage itself triggers chromatin modifications and remodeling, which are essential for efficient DNA repair and its coordination with transcription, replication, and epigenetic regulation to preserve genome function. While chromatin dynamics associated with double-strand break repair and nucleotide excision repair are well understood, those accompanying base excision repair (BER) remain comparatively poorly characterized. Yet, BER is responsible for eliminating a wide spectrum of chemically diverse and non-helix-distorting base modifications, arising from both endogenous and exogenous sources, and is implicated in numerous pathologies. This review examines how BER operates in the context of chromatin, with a focus on its interplay with other repair factors, chromatin modifications, and remodeling. It also explores the diversity of BER substrates, the blurred distinction between base lesions and programmed modifications, and the intricate link between BER, transcriptional regulation, and epigenetic reprogramming. Together, these insights highlight BER's pivotal role in maintaining genome stability, shaping transcriptional programs, and preventing disease.

Excision Repair↗

PubMed2026

Characterization of a Ku-binding motif in the C-terminal region of RAG2.

We applied an unsupervised interactome analysis with the RAG2 C-terminal region (R2CT) in v-abl pro-B cells undergoing V(D)J recombination. Mass-spectrometry analyses showed that Ku70 and Ku80 were among the top 10 hits. To further strengthen these observations, we performed Proximity Ligation Assay (PLA) and characterize the existence of a GFP-R2CT-Ku complex formation in cellulo. The interaction of several partners with Ku70/80 (Ku) through Ku-binding motifs (KBMs) in their sequences governs their enrolment in NHEJ repair complexes. Through sequence analysis, we identified a KBM within R2CT (R-KBM, amino acids 589-527). We confirmed by calorimetry a specific micromolar interaction between this RAG2 region and Ku70/80/DNA complex. The RAG2 motif KBM can be subdivided in two conserved parts that have no interaction individually. AlphaFold2 prediction coupled with molecular dynamic simulations indicate that the C-terminal part of the RAG2 motif interacts with Ku80 on the same site than the NHEJ factor XLF. These in silico analyses indicated that the N-terminal part of the RAG2 motif interacts with DNA adjacent to Ku with a major role of the K503 residue in agreement with disruption of the interaction observed with the K503E mutant. This study further extends the large ensemble of proteins recruited at DSBs by KBM motifs and substantiates the model of a tight coupling between DNA breakage and repair during V(D)J recombination, mediated by the Ku-RAG2 C-terminus interaction.

Ku Autoantigen↗

PubMed1978

Size and shape of mycoplasma virus MV-Lg-L 172 DNA.

Sedimentation of DNA of mycoplasma virus MV-Lg-L 172 in neutral and alkaline density gradients showed that the chromosome of this virus is most probably formed by a double-stranded circular DNA molecule with a molecular weight of approx. 10(7) daltons. These results were confirmed by direct electron microscopy of the viral DNA. Gamma-irradiation of the virus caused in its DNA single breaks on the average per each 66 eV of absorbed energy. Virus survival depended exponentially on the irradiation dose, D0 being between 60,000 and 70,000 rads. This dose induced on the average one single break in the DNA.

Acholeplasma laidlawii↗

PubMed2026

Retrotransposon activation during spermatogenesis achieves massive ecDNA biogenesis but rare integration.

Retrotransposon mobilization in germline cells enables the rewriting of genetic information to drive genome innovation, species evolution, and adaptation through the generation of de novo mutations. However, uncontrolled mobilization can cause DNA breaks and genome instability, often leading to sterility. How retrotransposon mobilization that can be retained for genome evolution persists despite negative outcomes of retrotransposon activity remains poorly understood. Here, we used Drosophila spermatogenesis as a model to investigate retrotransposon mobilization dynamics. Although many retrotransposon families are transcriptionally active, we found that the LTR retrotransposon nomad completes the full mobilization cascade (including mRNA export, protein translation, and reverse transcription) to produce double-stranded DNA (dsDNA) the most efficiently. Strikingly, despite successfully generating dsDNA, nomad rarely achieves genomic reintegration. Instead, its newly synthesized DNA predominantly forms extrachromosomal circular DNA (ecDNA). These findings show that retrotransposon-derived DNA largely remains as ecDNA. This could prevent widespread genomic integration during spermatogenesis, potentially preserving genome stability with the presence of limited retrotransposon activity.

Animals↗

PubMed1978

Transcription of rat liver deoxyribonucleic acid in vitro at low ionic strength.

1. When RNA polymerase is in excess over DNA, the single-stranded breaks of DNA can be recognized as initiation sites for the ezyme. On the other hand stabel initiation complexes (resistant to inhibition by heparin) are the most abundant under these conditions. The formation of these complexes needs double-stranded DNA. It seems that RNA sequences rich in cytidine are preferentially synthesized; since rat liver DNA is A + T-rich, the transcription thus appears not to be random with respect to the base composition of DNA. 2. When the template is in excess over the polymerase, the single-stranded gaps of DNA are preferentially transcribed by rat liver RNA polymerase B and native DNA regions by Escherichia coli RNA polymerase. 3. With a large excess of DNA over the polymerase, the enzyme activity is markedly inhibited. This inhibition is proportional to the concentration of double-stranded DNA ends, but it also depends on the presence of a contaminant of DNA, removed when DNA is banded in a CsCl gradient. This contaminant could be polyphosphates. Low concentrations of spermine completely reverse this inhibition, by enhancing the rate of RNA chain elongation. 4. Double-stranded RNA is synthesized in great abundance when RNA polymerase is in excess over native DNA. Besides a majority of symmetrical sequences, stable 'hairpins' can be found. Whereas the synthesis of symmetrical sequences is more prevalent in polymerase excess, it seems that the proportion of stable 'hairpins' in RNA is independent of the polymerase/DNA ratio.

Animals↗

PubMed1976

Mismatch correction in pneumococcal transformation: donor length and hex-dependent marker efficiency.

A hypothesis that preferential rejection of donor markers by the hex system of pneumococcus is due to lethal double-strand breaks has been examined in terms of its implications for the extent of the excision required. Experiments reported here were directed at asking whether hex-dependent marker efficiency depends on the length of the donor deoxyribonucleic acid (DNA). In the absence of intracellular competition for hex function, there was no detectable effect of DNA size on hex-dependent marker efficiency as donor DNA was sheared from greater than 1 x 107 daltons to 3.6 x 105 daltons. The latter DNA was purified by two successive velocity fractionations to ensure that the activity seen was representative of DNA of that size. Quantitative examination of the system shows that, for the lethal event hypothesis to be true, the excision step has to remove an average of 7,000 to 10,000 nucleotides. This figure is so much greater than that seen in other excision processes that alternate hypotheses should be considered. The presently known properties of the hex system can be accounted for by a model invoking the migratory features of type I restriction enzymes.

DNA Repair↗

PubMed2026

Chromosome-scale genome remodeling in tumor evolution: Copy number alterations and structural variants as two sides of the same coin.

Chromosome-scale genomic rearrangements are a dominant force in tumor evolution. Copy-number alterations (CNAs) and structural variants (SVs) constitute two complementary axes of this process. Although detection technologies now deliver near-comprehensive catalogs, technical resolution has outpaced conceptual integration. In this review, we frame CNAs and SVs as inextricable facets of chromosomal aberrations. They reshape cancer genomes through altered gene dosage and three-dimensional regulatory rewiring. CNAs quantify the gene-dosage imbalance, yet arise through mechanistically distinct routes. Segmental CNAs typically require chromosomal breakage, and therefore often coincide with SV junctions. By contrast, whole-chromosome aneuploidy and whole-genome doubling (WGD) primarily reflect mitotic or cytokinetic failure and can occur without local breakpoints, while nevertheless reshaping the karyotypic landscape and seeding subsequent structural complexity. SVs, in turn, range from unbalanced events that alter copy number to ostensibly balanced exchanges that predominantly rewire regulatory architecture. Despite their diverse and sometimes catastrophic architectures, SVs are ultimately rooted in double-strand break formation and error-prone resolution. By integrating CNAs and SVs within a unified mechanistic and functional framework, we aim to convert catalogs into concepts and distill the organizing principles that govern tumor genome evolution.

Humans↗

PubMed2025

Enhanced cleavage of genomic CCR5 using CASX2Max.

Development of novel CRISPR/Cas systems enhances opportunities for gene editing to treat infectious diseases, cancer, and genetic disorders. CasX2 (PlmCas12e) belongs to the class II CRISPR system derived from Planctomycetes, a non-pathogenic bacterium present in aquatic and terrestrial soils and offers several advantages as a potential therapeutic CRISPR system over Streptococcus pyogenes Cas9 (SpCas9) and Staphylococcus aureus Cas9 (SaCas9). These advantages include its smaller size, distinct protospacer adjacent motif (PAM) requirements, staggered cleavage cuts that promote homology-directed repair, and the absence of pre-existing immunity in humans. We compared the cleavage efficiency and double-stranded break repair characteristics between CasX2 and CasX2Max, a recently generated CasX2 variant with three amino acid substitutions, for targeting CCR5, a gene that encodes the CCR5 receptor important for HIV-1 infection. Two single guide RNAs (sgRNAs) were designed that flank the 32 bases deleted in the natural CCR5 ∆32 mutation. Nanopore sequencing demonstrated that CasX2 using sgRNAs with spacers of 17 nucleotides (nt), 20 nt or 23 nt in length were ineffective at cleaving genomic CCR5. In contrast, CasX2Max using sgRNAs with 20 nt and 23 nt spacer lengths, enabled cleavage of genomic CCR5. Structural modelling indicated that two of the CasX2Max amino acid substitutions enhanced sgRNA-DNA duplex stability, while the third improved DNA strand alignment within the catalytic site. These structural changes likely underlie the increased activity of CasX2Max in cellular gene excision. In sum, CasX2Max consistently outperformed native CasX2 across all assays and represents a superior gene-editing platform for therapeutic applications.

Humans↗

PubMed1976

Naturally occurring cross-links in yeast chromosomal DNA.

Chromosome-size yeast DNA molecules with a number average molecular weight (Mn) of 3-4 X 10(8) were isolated from sucrose gradients after sedimentation of lysed yeast spheroplasts. Resedimentation showed that the molecules were isolated without introducing appreciable single-strand or double-strand breaks. The presence of cross-links in these molecules was suggested by the observation that the apparent Mn in alkali was greater than expected for separated single strands. Since cross-linked molecules would have strands which fail to separate upon denaturation, this was tested more directly. Neutralization of alkaline denaturing conditions resulted in up to 70% of the intact molecules rapidly reforming duplex structures, as shown by equilibrium banding in CsCI. Experiments with larger E. coli DNA molecules (Mn = 5.2 X 10(8)) indicated that the conditions used were sufficient to denature completely molecules of this size. Results of enzyme treatments suggest that the cross-links are not RNA or protein. Experiments with density-labeled yeast DNA molecules showed that the rapid reformation of duplex DNA is not the consequence either of a bimolecular reaction between separated DNA strands or of intrastrand renaturation. The data indicate that when the yeast DNA molecules are completely denatured, the strands fail to separate. Hence they must be cross-linked. Experiments with sheared DNA show that there are small number of cross-links, one to four, permolecule.

Centrifugation, Density Gradient↗

PubMed1979

Specificity and mode of cleavage of the pH 4.0 endonuclease from adenovirus type 2 - infected KB cells.

Adenovirus type 2 or lambda DNA was digested with the pH 4.0 endonuclease, purified from adenovirus 2-infected KB cells. The enzyme produces a limit digest of approximate size in the range of 140-210 base pairs long. The termini of the DNA fragments generated by the endonuclease digestion had 3'-P and 5'-OH groups. The 3' and 5' end groups of the products were analyzed. Our data indicate that 3' end group was a purine (68-76%), dA occuring about twice the frequency of dG. The 5' end group was either dG or dC with equal frequency. Data obtained by treatment of the 5' labeled endonuclease product of lambda DNA with single-strand specific S1 nuclease from Asperigillus oryzae or exonuclease VII from Escherichia coli indicated that the majority of the products had a short 5' protruding ends. The mode of cleavage of this endonuclease seems to be through initial formation of several single-strand breaks with some base specificity. If these breaks are at close proximity on opposite strands, double-stranded fragments with protruding ends are generated.

Adenoviruses, Human↗