USP25 Elevates SHLD2-Mediated DNA Double-Strand Break Repair and Regulates Chemoresponse in Cancer.

DNA damage plays a significant role in the tumorigenesis and progression of the disease. Abnormal DNA repair affects the therapy and prognosis of cancer. In this study, it is demonstrated that the deubiquitinase USP25 promotes non-homologous end joining (NHEJ), which in turn contributes to chemoresistance in cancer. It is shown that USP25 deubiquitinates SHLD2 at the K64 site, which enhances its binding with REV7 and promotes NHEJ. Furthermore, USP25 deficiency impairs NHEJ-mediated DNA repair and reduces class switch recombination (CSR) in USP25-deficient mice. USP25 is overexpressed in a subset of colon cancers. Depletion of USP25 sensitizes colon cancer cells to IR, 5-Fu, and cisplatin. TRIM25 is also identified, an E3 ligase, as the enzyme responsible for degrading USP25. Downregulation of TRIM25 leads to an increase in USP25 levels, which in turn induces chemoresistance in colon cancer cells. Finally, a peptide that disrupts the USP25-SHLD2 interaction is successfully identified, impairing NHEJ and increasing sensitivity to chemotherapy in PDX model. Overall, these findings reveal USP25 as a critical effector of SHLD2 in regulating the NHEJ repair pathway and suggest its potential as a therapeutic target for cancer therapy.

SIRT2 promotes base excision repair by transcriptionally activating OGG1 in an ATM/ATR-dependent manner.

Sirtuin 2 (SIRT2) regulates the maintenance of genome integrity by targeting pathways of DNA damage response and homologous recombination repair. However, whether and how SIRT2 promotes base excision repair (BER) remain to be determined. Here, we found that independent of its catalytic activity SIRT2 interacted with the critical glycosylase OGG1 to promote OGG1 recruitment to its own promoter upon oxidative stress, thereby enhancing OGG1 promoter activity and increasing BER efficiency. Further studies revealed that SIRT2 was phosphorylated on S46 and S53 by ATM/ATR upon oxidative stress, and SIRT2 phosphorylation enhanced the SIRT2-OGG1 interaction and mediated the stimulatory effect of SIRT2 on OGG1 promoter activity. We also characterized 37 cancer-derived SIRT2 mutants and found that 5 exhibited the loss of the stimulatory effects on OGG1 transcription. Together, our data reveal that SIRT2 acts as a tumor suppressor by promoting OGG1 transcription and increasing BER efficiency in an ATM/ATR-dependent manner.

SMYD3 promotes endometrial cancer through epigenetic regulation of LIG4/XRCC4/XLF complex in non-homologous end joining repair.

Endometrial cancer (EC) stands as one of the most prevalent malignancies affecting the female genital tract, witnessing a rapid surge in incidence globally. Despite the well-established association of histone methyltransferase SMYD3 with the development and progression of various cancers, its specific oncogenic role in endometrial cancer remains unexplored. In the present study, we report that the expression level of SMYD3 is significantly upregulated in EC samples and associated with EC progression. Through meticulous in vivo and in vitro experiments, we reveal that depletion of SMYD3 curtails cell proliferation, migration, and invasion capabilities, leading to compromised non-homologous end joining repair (NHEJ) and heightened sensitivity of EC cells to radiation. Furthermore, our pathway enrichment analysis underscores the pivotal involvement of the DNA damage repair pathway in regulating EC progression. Mechanistically, in response to DNA damage, SMYD3 is recruited to these sites in a PARP1-dependent manner, specifically methylating LIG4. This methylation sets off a sequential assembly of the LIG4/XRCC4/XLF complex, actively participating in the NHEJ pathway and thereby fostering EC progression. Notably, our findings highlight the promise of SMYD3 as a crucial player in NHEJ repair and its direct correlation with EC progression. Intriguingly, pharmacological intervention targeting SMYD3 with its specific inhibitor, BCI-121, emerges as a potent strategy, markedly suppressing the tumorigenicity of EC cells and significantly enhancing the efficacy of radiotherapy. Collectively, our comprehensive data position SMYD3 as a central factor in NHEJ repair and underscore its potential as a promising pharmacological target for endometrial cancer therapy, validated through both in vitro and in vivo systems.

Synergistic anticancer effect by targeting CDK2 and EGFR-ERK signaling.

The EGFR-RAS-ERK pathway is one of the most important signaling cascades in cell survival, growth, and proliferation. Aberrant activation of this pathway is a common mechanism in various cancers. Here, we report that CDK2 is a novel regulator of the ERK pathway via USP37 deubiquitinase (DUB). Mechanistically, CDK2 phosphorylates USP37, which is required for USP37 DUB activity. Further, USP37 deubiquitinates and stabilizes ERK1/2, thereby enhancing cancer cell proliferation. Thus, CDK2 is able to promote cell proliferation by activating USP37 and, in turn, stabilizing ERK1/2. Importantly, combined CDK1/2 and EGFR inhibitors have a synergetic anticancer effect through the downregulation of ERK1/2 stability and activity. Indeed, our patient-derived xenograft (PDX) results suggest that targeting both ERK1/2 stability and activity kills cancer cells more efficiently even at lower doses of these two inhibitors, which may reduce their associated side effects and indicate a potential new combination strategy for cancer therapy.

Nuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation.

Cyclic GMP-AMP synthase (cGAS), initially identified as a cytosolic DNA sensor, detects DNA fragments to trigger an innate immune response. Recently, accumulating evidence reveals the presence of cGAS within the nucleus. However, the biological functions of nuclear cGAS are not fully understood. Here, we demonstrate that nuclear cGAS represses LINE-1 (L1) retrotransposition to preserve genome integrity in human cells. Mechanistically, the E3 ligase TRIM41 interacts with and ubiquitinates ORF2p to influence its stability, and cGAS enhances the association of ORF2p with TRIM41, thereby promoting TRIM41-mediated ORF2p degradation and the suppression of L1 retrotransposition. In response to DNA damage, cGAS is phosphorylated at serine residues 120 and 305 by CHK2, which promotes cGAS-TRIM41 association, facilitating TRIM41-mediated ORF2p degradation. Moreover, we show that nuclear cGAS mediates the repression of L1 retrotransposition in senescent cells induced by DNA damage agents. We also identify several cancer-associated cGAS mutations that abolish the suppressive effect on L1 retrotransposition by disrupting the CHK2-cGAS-TRIM41-ORF2p regulatory axis. Together, these findings indicate that nuclear cGAS exhibits an inhibitory function in L1 retrotransposition which could provide avenues for future interventions in both aging and tumorigenesis.

Mycobacterium tuberculosis suppresses host DNA repair to boost its intracellular survival.

Mycobacterium tuberculosis (Mtb) triggers distinct changes in macrophages, resulting in the formation of lipid droplets that serve as a nutrient source. We discover that Mtb promotes lipid droplets by inhibiting DNA repair responses, resulting in the activation of the type-I IFN pathway and scavenger receptor-A1 (SR-A1)-mediated lipid droplet formation. Bacterial urease C (UreC, Rv1850) inhibits host DNA repair by interacting with RuvB-like protein 2 (RUVBL2) and impeding the formation of the RUVBL1-RUVBL2-RAD51 DNA repair complex. The suppression of this repair pathway increases the abundance of micronuclei that trigger the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway and subsequent interferon-ß (IFN-ß) production. UreC-mediated activation of the IFN-ß pathway upregulates the expression of SR-A1 to form lipid droplets that facilitate Mtb replication. UreC inhibition via a urease inhibitor impaired Mtb growth within macrophages and in vivo. Thus, our findings identify mechanisms by which Mtb triggers a cascade of cellular events that establish a nutrient-rich replicative niche.

[TCOF1 Gene variation in Treacher Collins syndrome and evaluation of speech rehabilitation after bone bridge surgery].

Objective:By analyzing the clinical phenotypic characteristics and gene sequences of two patients with Treacher Collins syndrome（TCS）, the biological causes of the disease were determined. Then discuss the therapeutic effect of hearing intervention after bone bridge implantation. Methods:All clinical data of the two family members were collected, and the patients signed the informed consent. The peripheral blood of the proband and family members was extracted, DNA was extracted for whole exome sequencing, and Sanger sequencing was performed on the family members for the mutation site.TCOF1genetic mutations analysis was performed on the paitents. Then, the hearing threshold and speech recognition rate of family 2 proband were evaluated and compared under the sound field between bare ear and wearing bone bridge. Results:In the two pedigrees, the probands of both families presented with auricle deformity, zygomatic and mandibular hypoplasia, micrognathia, hypotropia of the eye fissure, and hypoplasia of the medial eyelashes. The proband of Family 1 also presents with specific features including right-sided narrow anterior nasal aperture and dental hypoplasia, which were consistent with the clinical diagnosis of Treacher Collins syndrome. Genetic testing was conducted on both families, and two heterozygous mutations were identified in the TCOF1 gene: c. 1350_1351dupGG（p. A451Gfs*43） and c. 4362_4366del（p. K1457Efs*12）, resulting in frameshift mutations in the amino acid sequence. Sanger sequencing validation of the TCOF1 gene in the parents of the proband in Family 1 did not detect any mutations. Proband 1 TCOF1 c. 1350_1351dupGG heterozygous variants have not been reported previously. The postoperative monosyllabic speech recognition rate of family 2 proband was 76%, the Categories of Auditory Performance（CAP） score was 6, and the Speech Intelligibility Rating（SIR） score was 4. Assessment using the Meaningful Auditory Integration Scale（MAIS） showed notable improvement in the patient's auditory perception, comprehension, and usage of hearing aids. Evaluation using the Glasgow Children's Benefit Inventory and quality of life assessment revealed significant improvements in the child's self care abilities, daily living and learning, social interactions, and psychological well being, as perceived by the parents. Conclusion:This study has elucidated the biological cause of Treacher Collins syndrome, enriched the spectrum of TCOF1 gene mutations in the Chinese population, and demonstrated that bone bridge implantation can improve the auditory and speech recognition rates in TCS patients.

SMYD2 inhibition-mediated hypomethylation of Ku70 contributes to impaired nonhomologous end joining repair and antitumor immunity.

DNA damage repair (DDR) is a double-edged sword with different roles in cancer susceptibility and drug resistance. Recent studies suggest that DDR inhibitors affect immune surveillance. However, this phenomenon is poorly understood. We report that methyltransferase SMYD2 plays an essential role in nonhomologous end joining repair (NHEJ), driving tumor cells adaptive to radiotherapy. Mechanically, in response to DNA damage, SMYD2 is mobilized onto chromatin and methylates Ku70 at lysine-74, lysine-516, and lysine-539, leading to increased recruitment of Ku70/Ku80/DNA-PKcs complex. Knockdown of SMYD2 or its inhibitor AZ505 results in persistent DNA damage and improper repair, which sequentially leads to accumulation of cytosolic DNA, and activation of cGAS-STING pathway and triggers antitumor immunity via infiltration and activation of cytotoxic CD8+ T cells. Our study reveals an unidentified role of SMYD2 in regulating NHEJ pathway and innate immune responses, suggesting that SMYD2 is a promising therapeutic target for cancer treatment.

Loss of the receptors ER, PR and HER2 promotes USP15-dependent stabilization of PARP1 in triple-negative breast cancer.

Poly(ADP-ribose) polymerase 1 (PARP1) is essential for the progression of several types of cancers. However, whether and how PARP1 is stabilized to promote genomic stability in triple-negative breast cancer (TNBC) remains unknown. Here, we demonstrated that the deubiquitinase USP15 interacts with and deubiquitinates PARP1 to promote its stability, thereby stimulating DNA repair, genomic stability and TNBC cell proliferation. Two PARP1 mutations found in individuals with breast cancer (E90K and S104R) enhanced the PARP1-USP15 interaction and suppressed PARP1 ubiquitination, thereby elevating the protein level of PARP1. Importantly, we found that estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) inhibited USP15-mediated PARP1 stabilization through different mechanisms. ER bound to the USP15 promoter to suppress its expression, PR suppressed the deubiquitinase activity of USP15, and HER2 abrogated the PARP1-USP15 interaction. The specific absence of these three receptors in TNBC results in high PARP1 levels, leading to increases in base excision repair and female TNBC cell survival.

The landscape of aging.

Aging is characterized by a progressive deterioration of physiological integrity, leading to impaired functional ability and ultimately increased susceptibility to death. It is a major risk factor for chronic human diseases, including cardiovascular disease, diabetes, neurological degeneration, and cancer. Therefore, the growing emphasis on "healthy aging" raises a series of important questions in life and social sciences. In recent years, there has been unprecedented progress in aging research, particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes. In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases, we review the descriptive, conceptual, and interventive aspects of the landscape of aging composed of a number of layers at the cellular, tissue, organ, organ system, and organismal levels.

Preclinical validation and phase I trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dNTP synthesis in multiple myeloma.

BACKGROUND: Aberrant DNA repair pathways contribute to malignant transformation or disease progression and the acquisition of drug resistance in multiple myeloma (MM); therefore, these pathways could be therapeutically exploited. Ribonucleotide reductase (RNR) is the rate-limiting enzyme for the biosynthesis of deoxyribonucleotides (dNTPs), which are essential for DNA replication and DNA damage repair. In this study, we explored the efficacy of the novel RNR inhibitor, 4-hydroxysalicylanilide (HDS), in myeloma cells and xenograft model. In addition, we assessed the clinical activity and safety of HDS in patients with MM. METHODS: We applied bioinformatic, genetic, and pharmacological approaches to demonstrate that HDS was an RNR inhibitor that directly bound to RNR subunit M2 (RRM2). The activity of HDS alone or in synergy with standard treatments was evaluated in vitro and in vivo. We also initiated a phase I clinical trial of single-agent HDS in MM patients (ClinicalTrials.gov: NCT03670173) to assess safety and efficacy. RESULTS: HDS inhibited the activity of RNR by directly targeting RRM2. HDS decreased the RNR-mediated dNTP synthesis and concomitantly inhibited DNA damage repair, resulting in the accumulation of endogenous unrepaired DNA double-strand breaks (DSBs), thus inhibiting MM cell proliferation and inducing apoptosis. Moreover, HDS overcame the protective effects of IL-6, IGF-1 and bone marrow stromal cells (BMSCs) on MM cells. HDS prolonged survival in a MM xenograft model and induced synergistic anti-myeloma activity in combination with melphalan and bortezomib. HDS also showed a favorable safety profile and demonstrated clinical activity against MM. CONCLUSIONS: Our study provides a rationale for the clinical evaluation of HDS as an anti-myeloma agent, either alone or in combination with standard treatments for MM. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03670173, Registered 12 September 2018.

Cytoplasmic PARP1 links the genome instability to the inhibition of antiviral immunity through PARylating cGAS.

Virus infection modulates both host immunity and host genomic stability. Poly(ADP-ribose) polymerase 1 (PARP1) is a key nuclear sensor of DNA damage, which maintains genomic integrity, and the successful application of PARP1 inhibitors for clinical anti-cancer therapy has lasted for decades. However, precisely how PARP1 gains access to cytoplasm and regulates antiviral immunity remains unknown. Here, we report that DNA virus induces a reactive nitrogen species (RNS)-dependent DNA damage and activates DNA-dependent protein kinase (DNA-PK). Activated DNA-PK phosphorylates PARP1 on Thr594, thus facilitating the cytoplasmic translocation of PARP1 to inhibit the antiviral immunity both in vitro and in vivo. Mechanistically, cytoplasmic PARP1 interacts with and directly PARylates cyclic GMP-AMP synthase (cGAS) on Asp191 to inhibit its DNA-binding ability. Together, our findings uncover an essential role of PARP1 in linking virus-induced genome instability with inhibition of host immunity, which is of relevance to cancer, autoinflammation, and other diseases.

The Roles of RNA Helicases in DNA Damage Repair and Tumorigenesis Reveal Precision Therapeutic Strategies.

DEAD-box RNA helicases belong to a large group of RNA-processing factors and play vital roles unwinding RNA helices and in ribosomal RNA biogenesis. Emerging evidence indicates that RNA helicases are associated with genome stability, yet the mechanisms behind this association remain poorly understood. In this study, we performed a comprehensive analysis of RNA helicases using multiplatform proteogenomic databases. More than 50% (28/49) of detected RNA helicases were highly expressed in multiple tumor tissues, and more than 60% (17/28) of tumor-associated members were directly involved in DNA damage repair (DDR). Analysis of repair dynamics revealed that these RNA helicases are engaged in an extensively broad range of DDR pathways. Among these factors is DDX21, which was prominently upregulated in colorectal cancer. The high expression of DDX21 gave rise to frequent chromosome exchange and increased genome fragmentation. Mechanistically, aberrantly high expression of DDX21 triggered inappropriate repair processes by delaying homologous recombination repair and increasing replication stress, leading to genome instability and tumorigenesis. Treatment with distinct chemotherapeutic drugs caused higher lethality to cancer cells with genome fragility induced by DDX21, providing a perspective for treatment of tumors with high DDX21 expression. This study revealed the role of RNA helicases in DNA damage and their associations with cancer, which could expand therapeutic strategies and improve precision treatments for cancer patients with high expression of RNA helicases. SIGNIFICANCE: The involvement of the majority of tumor-associated RNA helicases in the DNA damage repair process suggests a new mechanism of tumorigenesis and offers potential alternative therapeutic strategies for cancer.

Chrysin impairs genomic stability by suppressing DNA double-strand break repair in breast cancer cells.

Chrysin, a natural compound isolated from various plants, such as the blue passion flower (Passiflora caerulea L.), exhibits multiple pharmacological activities, such as antitumor, anti-inflammatory and antioxidant activities. Accumulating evidence shows that chrysin inhibits cancer cell growth by inducing apoptosis and regulating cell cycle arrest. However, whether chrysin is involved in regulating genomic stability and its underlying mechanisms in breast cancer cells have not been determined. Here, we demonstrated that chrysin impairs genomic stability in MCF-7 and BT474 cells, inhibits cell survival and enhances the sensitivity of MCF-7 cells to chemotherapeutic drugs. Further experiments revealed that chrysin impairs DNA double-strand break (DSB) repair, resulting in accumulation of DNA damage. Mechanistic studies showed that chrysin inhibits the recruitment of the key NHEJ factor 53BP1 and delays the recruitment of the HR factor RAD51. Thus, we elucidated novel regulatory mechanisms of chrysin in DSB repair and proposed that a combination of chrysin and chemotherapy has curative potential in breast cancers.

[Genotype and phenotype analysis of a family with Waardenburg syndrome type â caused by a novel mutation in PAX3 gene].

Objective:To identify gene mutation and analysis the association between clinical characterizes and the mutations in a family of Waardenburg syndrome （WS） type I in Yunnan, China. Methods:With informed consent, the proband with WS phenotype and his family members were given medical history collection, physical examination and audiological evaluation. Peripheral blood was obtained, genomic DNA was extracted, and deafness related genes were detected by high-throughput sequencing. Sanger sequencing was used to verify the mutation sites of proband and his family members. Results:C. 602C>G mutation in exon 5 of PAX3 gene was identified, which is nonsense mutation and may cause a truncated protein. The mutation cause 201 amino acid of the protein changed from serine to stop codon. According to the American College of Medical Genetics and Genomics （ACMG）, it is considered as Pathogenicity（PVS1+PM2+PP3）. This mutation has not been included in the database also not been reported in the literature. Conclusion:Combined with the results of clinical diagnosis and gene diagnosis, this mutation was considered as the cause of the disease. This study enriched mutation spectrum of PAX3 gene.

The deacetylation-phosphorylation regulation of SIRT2-SMC1A axis as a mechanism of antimitotic catastrophe in early tumorigenesis.

Improper distribution of chromosomes during mitosis can contribute to malignant transformation. Higher eukaryotes have evolved a mitotic catastrophe mechanism for eliminating mitosis-incompetent cells; however, the signaling cascade and its epigenetic regulation are poorly understood. Our analyses of human cancerous tissue revealed that the NAD-dependent deacetylase SIRT2 is up-regulated in early-stage carcinomas of various organs. Mass spectrometry analysis revealed that SIRT2 interacts with and deacetylates the structural maintenance of chromosomes protein 1 (SMC1A), which then promotes SMC1A phosphorylation to properly drive mitosis. We have further demonstrated that inhibition of SIRT2 activity or continuously increasing SMC1A-K579 acetylation causes abnormal chromosome segregation, which, in turn, induces mitotic catastrophe in cancer cells and enhances their vulnerability to chemotherapeutic agents. These findings suggest that regulation of the SIRT2-SMC1A axis through deacetylation-phosphorylation permits escape from mitotic catastrophe, thus allowing early precursor lesions to overcome oncogenic stress.

Lycorine hydrochloride suppresses stress-induced premature cellular senescence by stabilizing the genome of human cells.

Lycorine, a natural compound isolated from the traditional Chinese medicinal herb Lycoris radiata, exhibits multiple pharmacological effects, such as anti-inflammatory, antiviral, and anticancer effects. Accumulating evidence also indicates that lycorine might hold the potential to treat age-associated Alzheimer's disease. However, whether lycorine is involved in delaying the onset of cellular senescence and its underlying mechanisms has not been determined. Here, we demonstrate that the salt of lycorine, lycorine hydrochloride, significantly suppressed stress-induced premature cellular senescence (SIPS) by ~2-fold, as determined by senescence-associated beta-galactosidase (SA-ß-gal) staining and the expression of p16 and p21. In addition, pretreating cells with lycorine hydrochloride significantly inhibited the expression of CXCL1 and IL1α, two factors of the senescence-associated secreted phenotype (SASP) in SIPS cells. Further experiments revealed that lycorine hydrochloride promoted both the homologous recombination (HR) and nonhomologous end joining (NHEJ) pathways of DNA double-strand break (DSB) repair. Mechanistic studies suggested that lycorine hydrochloride treatment promoted the transcription of SIRT1 and SIRT6, critical longevity genes positively regulating both HR and NHEJ repair pathways, thereby stimulating DSB repair and stabilizing genomes. Inhibiting SIRT1 enzymatic activity abrogated the protective effect of lycorine hydrochloride on delaying the onset of SIPS, repairing DSBs, and restoring genome integrity. In summary, our work indicates that lycorine hydrochloride might hold therapeutic potential for treating age-associated diseases or promoting healthy aging by stabilizing genomes.

Rational combination therapy for hepatocellular carcinoma with PARP1 and DNA-PK inhibitors.

Understanding differences in DNA double-strand break (DSB) repair between tumor and normal tissues would provide a rationale for developing DNA repair-targeted cancer therapy. Here, using knock-in mouse models for measuring the efficiency of two DSB repair pathways, homologous recombination (HR) and nonhomologous end-joining (NHEJ), we demonstrated that both pathways are up-regulated in hepatocellular carcinoma (HCC) compared with adjacent normal tissues due to altered expression of DNA repair factors, including PARP1 and DNA-PKcs. Surprisingly, inhibiting PARP1 with olaparib abrogated HR repair in HCC. Mechanistically, inhibiting PARP1 suppressed the clearance of nucleosomes at DNA damage sites by blocking the recruitment of ALC1 to DSB sites, thereby inhibiting RPA2 and RAD51 recruitment. Importantly, combining olaparib with NU7441, a DNA-PKcs inhibitor that blocks NHEJ in HCC, synergistically suppressed HCC growth in both mice and HCC patient-derived-xenograft models. Our results suggest the combined inhibition of both HR and NHEJ as a potential therapy for HCC.

The SIRT6 activator MDL-800 improves genomic stability and pluripotency of old murine-derived iPS cells.

Cellular reprogramming is an emerging strategy for delaying the aging processes. However, a number of challenges, including the impaired genome integrity and decreased pluripotency of induced pluripotent stem cells (iPSCs) derived from old donors, may hinder their potential clinical applications. The longevity gene, Sirtuin 6 (SIRT6), functions in multiple biological processes such as the maintenance of genome integrity and the regulation of somatic cell reprogramming. Here, for the first time, we demonstrate that MDL-800, a recently developed selective SIRT6 activator, improved genomic stability by activating two DNA repair pathways-nonhomologous end joining (NHEJ) and base excision repair (BER) in old murine-derived iPSCs. More interestingly, we found that pretreating old murine iPSCs, which normally exhibit a restricted differentiation potential, with MDL-800 promoted the formation of teratomas comprised of all three germ layers and robustly stimulated chimera generation. Our findings suggest that pharmacological activation of SIRT6 holds great promise in treating aging-associated diseases with iPSC-based cell therapy.

Diosmetin enhances the sensitivity of radiotherapy by suppressing homologous recombination in endometrial cancer.

Radiotherapy is an essential treatment for endometrial cancer (EC), especially in advanced, metastatic, and recurrent cases. Combining radiotherapy, which mainly causes DNA double-strand breaks (DSBs), with small molecules targeting aberrantly activated homologous recombination (HR) repair pathways holds great potential for treating ECs in advanced stages. Here, we demonstrate that diosmetin (DIO), a natural flavonoid, suppresses HR, therefore inhibiting cell proliferation and enhancing the sensitivity of EC to radiotherapy. Clonogenic experiments revealed that combining DIO and X-ray significantly inhibited the viability of EC cells compared to cells treated with diosmetin or X-ray alone. The survival fraction of EC cells decreased to 40% when combining 0.4 Gy X-ray and 4 µM DIO; however, each treatment alone only caused death in approximately 15% and 22% of cancer cells, respectively. Further mechanistic studies showed that diosmetin inhibited the recruitment of RPA2 and RAD51, two critical factors involved in the HR repair pathway, upon the occurrence of DSBs. Thus, we propose that a combination of diosmetin and irradiation is a promising therapeutic strategy for treating endometrial cancer.