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The Fanconi anemia pathway is a key pathway involved in the repair of deoxyribonucleic acidinterstrand crosslinking damage, which chiefly includes the following four modules: lesion recognition, Fanconi anemia core complex recruitment, FANCD2–FANCI complex monoubiquitination, and downstream events (nucleolytic incision, translesion synthesis, and homologous recombination). Mutations or deletions of multiple Fanconi anemia genes in this pathway can damage the interstrand crosslinking repair pathway and disrupt primordial germ cell development and oocyte meiosis, thereby leading to abnormal follicular development. Premature ovarian insufficiency is a gynecological clinical syndrome characterized by amenorrhea and decreased fertility due to decreased oocyte pool, accelerated follicle atresia, and loss of ovarian function in women <40 years old. Furthermore, in recent years, several studies have detected mutations in the Fanconi anemia gene in patients with premature ovarian insufficiency. In addition, some patients with Fanconi anemia exhibit symptoms of premature ovarian insufficiency and infertility. The Fanconi anemia pathway and premature ovarian insufficiency are closely associated. Summary Sentence In summary, we conducted a comprehensive summary and analysis of the relationship between Fanconi anemia genes and premature ovarian insufficiency from the perspective of the Fanconi anemia pathway, in order to provide new ideas for the pathogenesis of premature ovarian insufficiency. Graphical Abstract

Background Human myeloma cell lines (HMCLs) are widely used for their representation of primary myeloma cells because they cover patient diversity, although not fully. Their genetic background is mostly undiscovered, and no comprehensive study has ever been conducted in order to reveal those details. Methods We performed whole-exon sequencing of 33 HMCLs, which were established over the last 50 years in 12 laboratories. Gene expression profiling and drug testing for the 33 HMCLs are also provided and correlated to exon-sequencing findings. Results Missense mutations were the most frequent hits in genes (92%). HMCLs harbored between 307 and 916 mutations per sample, with TP53 being the most mutated gene (67%). Recurrent bi-allelic losses were found in genes involved in cell cycle regulation ( RB1 , CDKN2C ), the NFκB pathway ( TRAF3 , BIRC2 ), and the p53 pathway ( TP53 , CDKN2A ). Frequency of mutations/deletions in HMCLs were either similar to that of patients (e.g., DIS3 , PRDM1 , KRAS) or highly increased (e.g., TP53 , CDKN2C , NRAS , PRKD2) . MAPK was the most altered pathway (82% of HMCLs), mainly by RAS mutants. Surprisingly, HMCLs displayed alterations in epigenetic (73%) and Fanconi anemia (54%) and few alterations in apoptotic machinery. We further identified mutually exclusive and associated mutations/deletions in genes involved in the MAPK and p53 pathways as well as in chromatin regulator/modifier genes. Finally, by combining the gene expression profile, gene mutation, gene deletion, and drug response, we demonstrated that several targeted drugs overcome or bypass some mutations. Conclusions With this work, we retrieved genomic alterations of HMCLs, highlighting that they display numerous and unprecedented abnormalities, especially in DNA regulation and repair pathways. Furthermore, we demonstrate that HMCLs are a reliable model for drug screening for refractory patients at diagnosis or at relapse.

Preserving a high degree of genome integrity and stability in germ cells is of utmost importance for reproduction and species propagation. However, the regulatory mechanisms of maintaining genome stability in the developing primordial germ cells (PGCs), in which rapid proliferation is coupled with global hypertranscription, remain largely unknown. Here, we find that mouse PGCs encounter a constitutively high frequency of transcription–replication conflicts (TRCs), which lead to R-loop accumulation and impose endogenous replication stress on PGCs. We further demonstrate that the Fanconi anemia (FA) pathway is activated by TRCs and has a central role in the coordination between replication and transcription in the rapidly proliferating PGCs, as disabling the FA pathway leads to TRC and R-loop accumulation, replication fork destabilization, increased DNA damage, dramatic loss of mitotically dividing mouse PGCs, and consequent sterility of both sexes. Overall, our findings uncover the unique source and resolving mechanism of endogenous replication stress during PGC proliferation, provide a biological explanation for reproductive defects in individuals with FA, and improve our understanding of the monitoring strategies for genome stability during germ cell development.

The Fanconi anemia (FA) pathway safeguards genomic stability through cell cycle regulation and DNA damage repair. The canonical tumor suppressive role of FA proteins in the repair of DNA damage during interphase is well established, but their function in mitosis is incompletely understood. Here, we performed a kinome‐wide synthetic lethality screen in FANCA−/− fibroblasts, which revealed multiple mitotic kinases as necessary for survival of FANCA‐deficient cells. Among these kinases, we identified the depletion of the centrosome kinase SIK2 as synthetic lethal upon loss of FANCA. We found that FANCA colocalizes with SIK2 at multiple mitotic structures and regulates the activity of SIK2 at centrosomes. Furthermore, we found that loss of FANCA exacerbates cell cycle defects induced by pharmacological inhibition of SIK2, including impaired G2‐M transition, delayed mitotic progression, and cytokinesis failure. In addition, we showed that inhibition of SIK2 abrogates nocodazole‐induced prometaphase arrest, suggesting a novel role for SIK2 in the spindle assembly checkpoint. Together, these findings demonstrate that FANCA‐deficient cells are dependent upon SIK2 for survival, supporting a preclinical rationale for targeting of SIK2 in FA‐disrupted cancers. Fanconi anemia (FA) pathway disruptions are common among sporadic cancers. Thus, synthetic lethal approaches exploiting FA pathway deficiencies may present novel opportunities for the rational design of patient‐tailored strategies to improve cancer treatment outcomes. This study identifies SIK2 kinase as a synthetic lethal target of multiple FA genes, including FANCA. Interestingly, mitotic roles of SIK2 appear to underlie this interaction.

Background Breast cancer is the most prevalent tumor entity in Li-Fraumeni syndrome. Up to 80% of individuals with a Li-Fraumeni-like phenotype do not harbor detectable causative germline TP53 variants. Yet, no systematic panel analyses for a wide range of cancer predisposition genes have been conducted on cohorts of women with breast cancer fulfilling Li-Fraumeni(-like) clinical diagnostic criteria. Methods To specifically help explain the diagnostic gap of TP53 wild-type Li-Fraumeni(-like) breast cancer cases, we performed array-based CGH (comparative genomic hybridization) and panel-based sequencing of 94 cancer predisposition genes on 83 breast cancer patients suggestive of Li-Fraumeni syndrome who had previously had negative test results for causative BRCA1, BRCA2, and TP53 germline variants. Results We identified 13 pathogenic or likely pathogenic germline variants in ten patients and in nine genes, including four copy number aberrations and nine single-nucleotide variants or small indels. Three patients presented as double-mutation carriers involving two different genes each. In five patients (5 of 83; 6% of cohort), we detected causative pathogenic variants in established hereditary breast cancer susceptibility genes (i.e., PALB2, CHEK2, ATM ). Five further patients (5 of 83; 6% of cohort) were found to harbor pathogenic variants in genes lacking a firm association with breast cancer susceptibility to date (i.e., Fanconi pathway genes, RECQ family genes, CDKN2A /p14 ARF , and RUNX1 ). Conclusions Our study details the mutational spectrum in breast cancer patients suggestive of Li-Fraumeni syndrome and indicates the need for intensified research on monoallelic variants in Fanconi pathway and RECQ family genes. Notably, this study further reveals a large portion of still unexplained Li-Fraumeni(-like) cases, warranting comprehensive investigation of recently described candidate genes as well as noncoding regions of the TP53 gene in patients with Li-Fraumeni(-like) syndrome lacking TP53 variants in coding regions.

Platinum‐based chemotherapy remains a cornerstone of glioma treatment, yet resistance driven by the Fanconi anaemia (FA) DNA repair pathway limits efficacy. Here, we identified betulinic acid (BA) as a potent inhibitor of FA pathway activation. BA pretreatment abrogated cisplatin‐induced monoubiquitination of FANCI/FANCD2 and disrupted their nuclear foci formation and interactions with downstream repair proteins (ERCC1, REV1 and BRCA1), leading to persistent DNA interstrand crosslinks without affecting intrastrand lesion repair. Biochemical analyses revealed that BA selectively suppressed UBE2T expression at the transcriptional level, without altering mRNA stability or protein degradation, thereby blocking the FANCL‐UBE2T‐mediated ID2 monoubiquitination cascade. In vivo, BA significantly enhanced the antitumour efficacy of cisplatin in xenograft models. Mechanistically, BA inhibited MAPK/ERK signalling, and pharmacological reactivation of ERK reversed BA‐induced suppression of UBE2T and tumour growth. Collectively, these findings uncover a previously unrecognised MAPK/ERK‐UBE2T‐FA axis in glioma and highlight BA as a potential adjuvant to overcome cisplatin resistance through transcriptional repression of UBE2T.

Fanconi anemia (FA) is caused by defects in cellular responses to DNA crosslinking damage and replication stress. Given the constant occurrence of endogenous DNA damage and replication fork stress, it is unclear why complete deletion of FA genes does not have a major impact on cell proliferation and germ-line FA patients are able to progress through development well into their adulthood. To identify potential cellular mechanisms that compensate for the FA deficiency, we performed dropout screens in FA mutant cells with a whole genome guide RNA library. This uncovered a comprehensive genome-wide profile of FA pathway synthetic lethality, including POLI and CDK4. As little is known of the cellular function of DNA polymerase iota (Pol ι), we focused on its role in the loss-of-function FA knockout mutants. Loss of both FA pathway function and Pol ι leads to synthetic defects in cell proliferation and cell survival, and an increase in DNA damage accumulation. Furthermore, FA-deficient cells depend on the function of Pol ι to resume replication upon replication fork stalling. Our results reveal a critical role for Pol ι in DNA repair and replication fork restart and suggest Pol ι as a target for therapeutic intervention in malignancies carrying an FA gene mutation.

Although the 5-year survival rate of patients diagnosed with nonmuscle invasive bladder cancer (NMIBC) has reached 85%, more than 50% of patients suffer from frequent recurrences. To identify molecular targets associated with recurrence of NMIBC, we analyzed gene expression data and found that FOXM1 and FANCD2 were involved in recurrence. Therefore, we investigated how these genes were involved in the mechanism of recurrence and confirmed their usefulness as biomarkers. Investigation have shown that FOXM1 directly regulated the transcription of FANCD2, which is the key gene of the Fanconi anemia (FA) pathway. Depletion of FOXM1 resulted in DNA repair defects in the FA pathway and in decreased resistance to chemotherapy. Thus, the FANCD2-associated FA pathway activated by FOXM1 is an important mechanism involved in chemotherapy-related recurrence. In conclusion, FOXM1 and FANCD2 can be used as prognostic factors that are associated with high risk of recurrence and with anticancer drug resistance properties in NMIBC patients.

Objectives Resistance to platinum-based chemotherapy in bladder cancer is closely associated with activation of the Fanconi anemia (FA) DNA interstrand crosslink repair pathway. Identifying pharmacological inhibitors of FA signaling may improve therapeutic response. We investigated the effects of the natural compound toosendanin (TSN) on FA pathway regulation in this study. Methods Bladder cancer cell lines (T24, RT4, J82) were pretreated with TSN and exposed to ultraviolet C (UVC). FANCI/FANCD2 monoubiquitination, FANCD2 nuclear foci, FA core gene expression, and JAK/STAT1 signaling were quantified. A T24 xenograft model was used to validate FA pathway inhibition in vivo. Statistical analyses were performed using one-way ANOVA followed by Tukey’s post-hoc test (mean ± SD; n = 3 independent replicates; Shapiro–Wilk test for normality). Results TSN reduced UVC-induced 58% FANCI (P = 0.004, n = 3) and 77% FANCD2 monoubiquitination (P = 0.004, n = 3) in bladder cancer cells, and decreased FANCD2 foci-positive nuclei by 27% (P = 0.015, n = 3). Co-immunoprecipitation assays further revealed that TSN disrupted 56% interaction between the FANCI-FANCD2 complex and the key scaffold protein SLX4 (FANCP) (P = 0.002, n = 6). TSN down-regulated FA core genes (FANCA, FANCC, FANCF, FANCM) by 30 to 65% (all P < 0.05, n = 3) as well as decreased STAT1 phosphorylation by 45% (P = 0.013, n = 3) and the binding capacity of STAT1 on these FA genes’ promoter by 33% to 47% (all P < 0.05, n = 3). In xenograft tumors, TSN also reduced 70% FANCI (P = 0.007, n = 3) and 45% FANCD2 monoubiquitination (P = 0.011, n = 3) as well as expression of FANCA, FANCC, FANCF, FANCM by 26% to 38% (all P < 0.05, n = 3). TSN selectively sensitized bladder cancer cells to UVC-induced cytotoxicity (IC50 decreased 35%, P = 0.026, n = 3), without affecting the viability of human urothelial cell SV-HUC-1 cells or lung adenocarcinoma A549 cells (both P > 0.05, n = 3). Conclusion TSN inhibits FA DNA repair signaling in bladder cancer by suppressing JAK/STAT1-mediated FA core gene transcription, supporting its potential as a combinatorial agent to overcome cisplatin resistance. Graphical Abstract

Background Individuals diagnosed with Fanconi anemia (FA), an uncommon disorder characterized by chromosomal instability affecting the FA signaling pathway, exhibit heightened vulnerability to the onset of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Methods Herein, we employed diverse bioinformatics and statistical analyses to investigate the potential associations between the expression/mutation patterns of FA pathway genes and MDS/AML. Results The study included 4295 samples, comprising 3235 AML and 1024 MDS from our and nine other online cohorts. We investigated the distinct proportion of race, age, French-American-British, and gender factors. Compared to the FA wild-type group, we observed a decrease in the expression of FNACD2, FANCI, and RAD51C in the FA mutation group. The FA mutation group exhibited a more favorable clinical overall survival prognosis. We developed a random forest classifier and a decision tree based on FA gene expression for cytogenetic risk assessment. Furthermore, we created an FA-related Nomogram to predict survival rates in AML patients. Conclusions This investigation facilitates a deeper understanding of the functional links between FA and MDS/AML.