Nijmegen Breakage Syndrome Research Articles

NBS1 dePARylation by NUDT16 is critical for DNA double-strand break repair.

NBS1, a protein linked to the autosomal recessive disorder Nijmegen breakage syndrome, plays an essential role in the DNA damage response and DNA repair. Despite its importance, the mechanisms regulating NBS1 and the impact of this regulation on DNA repair processes remain obscure. In this study, we discovered a new post-translational modification of NBS1, ADP-ribosylation. This modification can be removed by the NUDT16 hydrolase. The loss of NUDT16 results in a reduction of NBS1 protein levels due to NBS1 PARylation-dependent ubiquitination and degradation, which is mediated by the PAR-binding E3 ubiquitin ligase, RNF146. Importantly, ADP-ribosylation of NBS1 is crucial for its localization at DSBs and its involvement in homologous recombination (HR) repair. Additionally, the NUDT16-NBS1 interaction is regulated in response to DNA damage, providing further rationale for NBS1 regulation by NUDT16 hydrolase. In summary, our study unveils the critical role of NUDT16 in governing both the stability of NBS1 and recruitment of NBS1 to DNA double-strand breaks, providing novel insights into the regulation of NBS1 in the HR repair pathway.

Update on Recommendations for Cancer Screening and Surveillance in Children with Genomic Instability Disorders.

Genomic instability disorders are characterized by DNA or chromosomal instability resulting in various clinical manifestations including developmental anomalies, immunodeficiency, and increased risk to develop cancers beginning in childhood. Many of these genomic instability disorders also present with exquisite sensitivity to anticancer treatments such as ionizing radiation and chemotherapy, which may further increase the risk of second cancers. In July 2023, the American Association of Cancer Research held the second Childhood Cancer Predisposition Workshop where multidisciplinary international experts discussed, reviewed, and updated recommendations for children with cancer predisposition syndromes. This article will discuss childhood cancer risks and surveillance recommendations for the group of genomic instability disorders with predominantly recessive inheritance, including the DNA repair disorders ataxia telangiectasia, Nijmegen breakage syndrome, Fanconi anemia, Xeroderma Pigmentosum, Bloom syndrome, and Rothmund-Thomson syndrome, as well as the telomere biology disorders and mosaic variegated aneuploidy. Recognition of children with genomic instability disorders is important in order to make the proper diagnosis, enable genetic counseling, and inform cancer screening, cancer risk reduction, and choice of anti-cancer therapy.

Genetic hallmarks and clinical implications of chromothripsis in childhood T-cell acute lymphoblastic leukemia

Chromothripsis (cth) is a form of genomic instability leading to massive de novo structural chromosome rearrangements in a one-time catastrophic event. It can cause cancer-promoting alterations, such as loss of sequences for tumor-suppressor genes, formation of oncogenic fusions, and oncogene amplifications. We investigated the genetic background and clinical significance of cth in childhood T-cell acute lymphoblastic leukemia (T-ALL) patients. For this purpose, whole-genome copy number alterations were analyzed in 173 children with newly diagnosed T-ALL using high-density microarrays. Cth was identified in 10 T-ALL samples (5.78%). In six of them, cth occurred in a constitutional background of Nijmegen breakage syndrome (n = 5) or Li-Fraumeni syndrome (n = 1). Cth generated alterations, including deletions of CDKN2A/B (n = 4) and EZH2 (n = 4), amplifications of CDK6 (n = 2), and NUP214::ABL1 and TFG::GPR128 fusions. Cth-positive leukemias exhibited deletions involving the tumor-suppressor genes RB1 (n = 3), TP53 (n = 1) and MED12 (n = 2). Cth-positive T-ALL patients had a lower probability of 5-year overall survival (OS) [0.56 vs. 0.81; hazard ratio (HR) = 4.14 (1.42–12.02) p = 0.017] as did 5-year event-free survival [0.45 vs. 0.74; HR = 3.91 (1.52–10.08); p = 0.012]. Chromothripsis is an infrequent genomic phenomenon in pediatric T-ALL but is significantly associated with cancer-predisposing syndromes and may associate with inferior prognosis.

NFS-01. EXTREMELY RARE CASE OF CHILDREN WITH NIJMEGEN BREAKAGE SYNDROME AND MEDULLOBLASTOMA – A THERAPEUTIC CHALLENGE

Abstract BACKGROUND Nijmegen Breakage Syndrome (NBS) is an autosomal recessive inherited disorder characterized by DNA repair abnormalities. It manifests with heightened sensitivity to radiotherapy (RT) and predisposes individuals to neoplastic diseases. Antineoplastic treatment in NBS patients is particularly challenging due to concurrent immune disorders, intense toxicities, and contraindications for RT. Hematologic disorders, especially lymphomas, are among the most prevalent malignancies in NBS patients. Solid tumors in NBS are extremely rare, with only two pediatric cases documented in the literature, both succumbing due to severe complications of treatment. METHODS A review and analysis of the medical documentation of a child with NBS and MB treated at the Department of Pediatrics, Hematology, and Oncology, Gdansk, Poland, were conducted. RESULTS A genetically confirmed NBS girl displaying typical phenotypic features presents symptoms at the age of 2 years, such as headaches, reluctance to walk, and drowsiness. Imaging confirmed a tumor in the left cerebellar hemisphere, measuring 40x33x30mm, displaying radiological features consistent with Medulloblastoma (MB). The patient underwent gross total resection of the tumor. The pathology revealed a desmoplastic type of MB with SHH activation, TP53 wild type, and ongoing molecular analysis. Postoperative imaging confirmed clinical remission, and cerebrospinal fluid examination was negative. Considering the substantial toxicities of chemotherapy in NBS patients and the contraindications for RT, the patient received chemotherapy with reduced cytostatic doses. Treatment was complicated by profound and prolonged myelosuppression and infections. Currently, after completing six cycles of chemotherapy, the patient is still in remission. To maintain remission and address NBS, the patient will receive allogeneic bone marrow transplantation from a 9/10 HLA-matched unrelated donor. CONCLUSIONS Managing patients with NBS, complicated by neoplastic diseases, is exceptionally demanding and necessitates an individualized multidisciplinary approach. Modern diagnostic and therapeutic methods enhance the prospects of reducing the toxicity of oncologic treatment, improving quality of life, and extending overall survival.

A Rare Case of Early T-Precursor Lymphoblastic Lymphoma (ETP-LBL) in a Child With Nijmegen Breakage Syndrome.

Lymphoblastic lymphoma (LBL) with an early T-cell precursor phenotype has only been rarely reported. Nijmegen breakage syndrome (NBS) is an inherited chromosomal instability disorder with known predisposition to malignancies that is very rare as well. We report a case of early T-precursor LBL (ETP-LBL) in a patient with NBS, a rare combination that has not been reported. We raise the question of whether a chromosomal instability disorder such as NBS increases the propensity for early T-precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL), given that ETP-ALL has been shown to have increased genomic instability compared to T-ALL.

9 Emergence of γδ+ T-cell Acute Leukemia Following Hematopoietic Stem Cell Transplant in a Patient with Nijmegen Breakage Syndrome

9 Emergence of γδ+ T-cell Acute Leukemia Following Hematopoietic Stem Cell Transplant in a Patient with Nijmegen Breakage Syndrome

Germ line genetic NBN variation and predisposition to B-cell acute lymphoblastic leukemia in children

AbstractBiallelic mutation in the DNA-damage repair gene NBN is the genetic cause of Nijmegen breakage syndrome, which is associated with predisposition to lymphoid malignancies. Heterozygous carriers of germ line NBN variants may also be at risk for leukemia development, although this is much less characterized. By sequencing 4325 pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL), we systematically examined the frequency of germ line NBN variants and identified 25 unique, putatively damaging NBN coding variants in 50 patients. Compared with the frequency of NBN variants in gnomAD noncancer controls (189 unique, putatively damaging NBN coding variants in 472 of 118 479 individuals), we found significant overrepresentation in pediatric B-ALL (P = .004; odds ratio, 1.8). Most B-ALL–risk variants were missense and cluster within the NBN N-terminal domains. Using 2 functional assays, we verified 14 of 25 variants with severe loss-of-function phenotypes and thus classified these as nonfunctional or partially functional. Finally, we found that germ line NBN variant carriers, all of whom were identified as heterozygous genotypes, showed similar survival outcomes relative to those with wild type status. Taken together, our findings provide novel insights into the genetic predisposition to B-ALL, and the impact of NBN variants on protein function and suggest that heterozygous NBN variant carriers may safely receive B-ALL therapy. These trials were registered at www.clinicaltrials.gov as #NCT01225874, NCT00075725, NCT00103285, NCI-T93-0101D, and NCT00137111.

Defective antibody production in double-strand DNA breakage syndromes: insights and implications

DNA double-strand breakage (DSB) syndrome are rare monogenic inborn errors of immunity with a vast spectrum of manifestations. In addition to a high predisposition to malignancies, these patients are also at risk of recurrent, severe, or opportunistic infections. Therefore, monitoring of immunoglobulin levels and responses to vaccination, as well as interventions such as immunoglobulin replacement therapy should be considered to improve the patients’ outcomes. As DNA double-strand breakage repair pathways have a great impact on lymphocyte development through involvement in the generation of B and T cell receptors, disruption in one of their components may lead to genomic instability, aberrant B-cell receptor (BCR)/T-cell receptor (TCR) development, impaired B cell lymphocyte development and antibody production. The aim of this review is to describe the most common of DBSs, such as ataxia telangiectasia (AT), AT-like disorder (ATLD), Nijmegen breakage syndrome (NBS), Nijmegen breakage syndrome-like disorder (NBSLD), Bloom syndrome (BS), Fanconi anemia (FA) and some others with a focus on the role of DNA repair proteins in the development of humoral immunity. We also describe the immunoglobulin profile, recommendations for diagnosis, screening, and interventions for the ideal management of affected patients.

Immunodeficiency masks: a complex diagnostic case of Nijmegen breakage syndrome

Purpose. The purpose of the study is to show the importance of a multidisciplinary approach in the early verification of the primary immunodeficiency — Nijmegen breakage syndrome. A girl was admitted with complaints of daily productive cough, persistent obstruction of nasal breathing, mucopurulent discharge, recurrent respiratory tract infections for three years. From the age of 2, she suffered from protracted recurrent respiratory infections, repeatedly received inpatient treatment with systemic antibiotic therapy with insufficient effect in the form of maintaining complaints. When examining according to CT scan of the chest — single atelectasis, ground glass areas. Immunodeficiency states were excluded at the place of residence. On examination: phenotypic features of the type of «bird-like» face — sloping forehead, middle part of the face protruding forward, beak-shaped nose, large ears. Physical development is low: weight and height indicators are less than the 3rd percentile. From the nasal passages mucopurulent discharge, productive cough. Auscultatory — moist rales in all lung fields. For other organs and systems — without features. On examination: deep T-cell lymphopenia, according to CT scan signs of pansinusitis, bilateral otitis media; post-inflammatory pneumofibrotic changes. According to the results ofspirometry — mixed lesions. According to the results of immunological and genetic additional examination, the immunodeficiency state — Nijmegen breakage syndrome was verified, constant anti-inflammatory, antibacterial and antifungal, immunoglobulin replacement therapy was initiated.Conclusion. The presented clinical observation reflects the features of the course of the Nijmegen breakage syndrome. This example demonstrates the diagnostic complexity in verifying the diagnosis and shows the great importance of a multidisciplinary approach for the timely initiation of appropriate therapy, which, in turn, affects the severity of the disease and quality of life.

Broncho-obstructive syndrome in pediatrician’s practice (clinical cases)

Background. With the development of broncho-obstructive syndrome (BOS), spasm, edema, hypercrinia and bronchial dyscrinia occur. Increasing airflow resistance can complicate the course of diseases of the respiratory system. Broncho-obstructive syndrome coexists many pathologies, including cardiovascular diseases, gastrointestinal diseases and other abnormal developments of internal organs. The causes of this syndrome are diverse, including bronchial asthma, abnormal developments of the bronchopulmonary system, gastroesophageal reflux, cystic fibrosis and congenital heart diseases. The purpose of this study was to analyze and describe clinical cases of pediatric patients with BOS.Clinical cases description. The article presents clinical cases of patients who were treated at the State Budgetary Healthcare Institution of Republic of Crimea “Republic Children’s Clinical Hospital” at different times, who developed BOS against the background of Nijmegen Breakage Syndrome and aspiration of a foreign body (feather from a pillow) into the bronchi. Both clinical cases show the importance of comprehensive, and most importantly, timely diagnostic procedure. In clinical case No. 1, the medical history of patient N. with Nijmegen Breakage Syndrome is described. The pathology was revealed owing to a comprehensive diagnostic procedure. Representatives of patient N. appealed to the State Budgetary Healthcare Institution of Republic of Crimea “Republic Children’s Clinical Hospital” in connection with the development of symptoms of bronchial obstruction. Clinical case No. 2 describes the untimely diagnosis of a radiolucent bronchial foreign body. In this situation, the ambiguity of the clinical picture and, as a result, the search for other pathologies cost the child his life.Conclusion. Broncho-obstructive syndrome is associated with a variety of pathologies that are not limited to problems with the respiratory system. It is important to be able to identify symptoms in patients that will indicate the cause of the developed BOS.

Nijmegen breakage syndrome: 25-year experience of diagnosis and treatment in Ukraine.

Nijmegen breakage syndrome (NBS) is an autosomal recessive disorder, characterized by microcephaly, immunodeficiency, and impaired DNA repair. NBS is most prevalent among Slavic populations, including Ukraine. Our study aimed to comprehensively assess the prevalence, diagnosis, clinical data, immunological parameters, and treatment of NBS patients in Ukraine. We conducted a retrospective review that included 84 NBS patients from different regions of Ukraine who were diagnosed in 1999-2023. Data from the Ukrainian Registry of NBS and information from treating physicians, obtained using a developed questionnaire, were utilized for analysis. Among 84 NBS patients, 55 (65.5%) were alive, 25 (29.8%) deceased, and 4 were lost to follow-up. The median age of patients was 11 years, ranging from 1 to 34 years. Most patients originate from western regions of Ukraine (57.8%), although in recent years, there has been an increase in diagnoses from central and southeastern regions, expanding our knowledge of NBS prevalence. The number of diagnosed patients per year averaged 3.4 and increased from 2.7 to 4.8 in recent years. The median age of NBS diagnosis was 4.0 years (range 0.1-16) in 1999-2007 and decreased to 2.7 in the past 6 years. Delayed physical development was observed in the majority of children up to the age of ten years. All children experienced infections, and 41.3% of them had recurrent infections. Severe infections were the cause of death in 12%. The second most common clinical manifestation of NBS was malignancies (37.5%), with the prevalence of lymphomas (63.3%). Malignancies have been the most common cause of death in NBS patients (72% of cases). Decreased levels of CD4+ and CD19+ were observed in 89.6%, followed by a reduction of CD3+ (81.8%) and CD8+ (62.5%). The level of NK cells was elevated at 62.5%. IgG concentration was decreased in 72.9%, and IgA - in 56.3%. Immunoglobulin replacement therapy was administered to 58.7% of patients. Regular immunoglobulin replacement therapy has helped reduce the frequency and severity of severe respiratory tract infections. Improvements in diagnosis, including prenatal screening, newborn screening, monitoring, and expanding treatment options, will lead to better outcomes for NBS patients.

Neurological involvement in patients with primary immunodeficiency.

Primary immunodeficiency diseases (PID) are defined by recurrent infections, allergies, autoimmunity, and malignancies. Neurologic symptoms are one of the major components of some immunodeficiency syndromes, such as Ataxia-Telangiectasia (AT), Nijmegen breakage syndrome (NBS), and Purine Nucleoside Phosphorylase (PNP) deficiency, which are considered as the primary involvement. Various pathological mechanisms, DNA repair disorders, metabolic abnormalities, and autoimmune phenomena have also been linked with neurological conditions. We retrospectively assessed the neurological involvement in 108 patients out of 6000 with PID in this study. The female/male ratio of the cases was 49/59, and the median age was 13 years (min = 1; max = 60). Neurological problems were detected at a median age of 7 years (min = 0.5; max = 30). Di George Syndrome (DGS) and CVID (common variable immunodeficiency) were the most common diseases in our cohort (n = 31, 30% and n = 30, 27%, respectively). The most frequent outcomes were cognitive delay (n = 63, 58%), epilepsy (n = 25, 23%), and ataxia (n = 20, 18%). Central nervous system involvement was found in 99% of the patients (n = 107), and peripheral nervous system complication was found in only one patient with CVID and chronic inflammatory demyelinating polyneuropathy (CDIP). Cranial MRI was found to be abnormal in 74% (n = 80) of the patients. MRI findings included cerebellar atrophy (n = 33, 34%), white matter lesion (n = 27, 28.4%), cerebral atrophy (n = 21, 22.3%), gray matter lesion (n = 6, 6.3%), hydrocephalus (n = 5, 5,3%), and pituitary gland lesion (n = 3, 3.2%), intracranial hemorrhage (n = 3, 3%), intracranial vasculitis (n = 3, 2.7%), and arterio-venous malformation (n = 1, 0,9%). Primary involvement (a component of the disease) was 60% (n = 65), and secondary (infection or autoimmunity) and tertiary involvements (structural or incidental lesions) contributed 20% (n = 20) each in the patients. In this study, we describe the various neurologic findings of patients with PID. The neurologic presentation may represent the initial manifestation of certain types of PID. Early diagnosis and treatment are essential to prevent or reduce further neurologic damages.

Liver transplantation for nijmegen breakage syndrome with hepatic malignity and hepatopulmonary syndrome after bone marrow transplantation: a case report

Liver transplantation for nijmegen breakage syndrome with hepatic malignity and hepatopulmonary syndrome after bone marrow transplantation: a case report

Suppression of NBS1 Upregulates CyclinB to Induce Olaparib Sensitivity in Ovarian Cancer.

Background: Deficiencies in DNA damage repair responses promote chemotherapy sensitivity of tumor cells. The Nibrin homolog encoding gene Nijmegen Breakage Syndrome 1 (NBS1) is a crucial component of the MRE11-RAD50-NBN complex (MRN complex) and is involved in the response to DNA double-strand breaks (DSBs) repair that has emerged as an attractive strategy to overcome tumor drug resistance, but the functional relationship between NBS1 regulated DNA damage repair and cell cycle checkpoints has not been fully elucidated. Methods: In this study, lentivirus-mediated RNAi was used to construct NBS1-downregulated cells. Flow cytometry, qPCR, and immunohistochemistry were used to explore the regulatory relationship between NBS1 and CyclinB in vivo and in vitro. Results: Our findings suggest that NBS1 deficiency leads to defective homologous recombination repair. Inhibition of NBS1 expression activates CHK1 and CyclinB signaling pathways leading to cell cycle arrest and sensitizes ovarian cancer cells to Olaparib treatment in vitro and in vivo. NBS1-deficient ovarian cancer cells tend to maintain sensitivity to chemotherapeutic drugs through activation of cell cycle checkpoints. Conclusions: NBS1 may be a potential therapeutic target for epithelial ovarian cancer as it plays a role in the regulation of the DNA damage response and cell cycle checkpoints. Suppression of NBS1 upregulates CyclinB to induce Olaparib sensitivity in ovarian cancer.

Role of the DNA Repair Machinery in Childhood B-Lineage Acute Lymphoblastic Leukemia: Aberrations of NBS1, Fancd2, Palb2 Genes and Expression of BRCA1 and BRCA2

Background. Successful treatment of B-lineageAcute Lymphoblastic Leukemia (B-ALL) in children has been related to novel biological findings and a better supportive therapy. Genomic aberrations have a major role in development of ALL and in the treatment response. Conventional treatment is based on chemotherapy, mainly acting on the structure of DNA in both leukemic and host cells. The result is a complete achievement of durable remission and/or a high incidence of toxicity. The role of DNA repair machinery in the occurrence of de novo or relapsed ALL and of high-grade toxicity is still unclear. We decide to dissect genes involved in the Fanconi Anemia (FA) pathway ( BRCA1, BRCA2, FANCD2 and PALB2), which cooperates with the Nijmegen breakage syndrome ( NBS1) gene. We evaluate the correlation of DNA repair machinery alterations with occurrence of relapse and/or with severe (III-IV grade - CTCAE) toxicity during chemotherapy treatment. Materials and Methods.The study was approved by the Local Clinical Research Ethics Committee (Catania-1). Written informed consents were obtained from the parents of each child involved in this research. We analyzed bone marrow (BM) samples from diagnosis and remission (Dx/Rem) of 111 children with B-ALL, diagnosed and treated at the Center of Pediatric Hematology Oncology, Catania Italy, from 2000 to 2017. These children were enrolled in three consecutive protocols of Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) [AIEOP-BFM ALL 2000; AIEOP-R 2006; AIEOP BFM ALL 2009]. Biological subgroups were as follow: 16 children presenting with t(1;19); 48 with t(12;21), 9 with t(9;22)/Ph+, 5 with a KMT2A (formerly MLL)rearrangement and 33 defined as “B-Others”. Traditional PCR method was used to determinate the NBS1 mutations in exons 3-6, followed by Sanger sequencing. FANCD2 and PALB2 mutations were investigated by multiplex ligation-dependent probe amplification (MLPA). Samples from healthy donors were used as wild-type controls. A real-time PCR assay was applied to evaluate the BRCA1 and BRCA2 genes expression using the SYBR green, fluorescent dye. We used specific primers for BRCA1 exons 14-15 and BRCA2 exons 15-16, respectively. The expression of BRCA1 and BRCA2 was determined as high (H) or low (L) using the Mean and the Median of fold change (FC) as cut-off. Results. Fifty-four patients (48%) out of 111 had more than one episode of severe toxicity during chemotherapy treatment. Twenty-one children (19%) with B-ALL out of 111 experienced the disease recurrence. The NBS1 polymorphism (rs1805794 SNP_G>C) was found in 28% of the patients enrolled in the study and showed a protective role against severe toxicity (p<0.05 ): only 10 of 54 patients, who experienced high grade toxicity, had this polymorphism. This protective effect was confirmed in the subgroup with t(12;21) positive B-ALL (p<0.05). There were no statistically significant relationships between NBS1 and relapse or between FANCD2/PALB2 aberrations and B-ALL toxicity/recurrence. At diagnosis, children with high expression of both BRCA genes ( BRCA1-H/ BRCA2-H) showed a correlationwith an increased incidence of severe toxicity:17 patients with severe toxicity out of 27 BRCA1-H/ BRCA2-H cases vs 10 out of 28 BRCA1-L/ BRCA2-L (p<0.05 ). At remission, high BRCA1 expression ( BRCA1-H) appears to be related to an increased risk of relapse, albeit not statistically significant (p=0.17) . BRCA2-H is associated with a higher incidence of recurrence than BRCA2-L (p<0.03): 8 cases with relapse out of 22 (BRCA2-H ) vs 13 out of 88 (BRCA2-L ). More importantly, we observed that cases with BRCA1-H /BRCA2-Hat remission are statistically significant associated with relapse: 3 children presented a relapseout of 6 cases with BRCA1-H/ BRCA2-H vs 8 out of 65 cases with BRCA1-L /BRCA2-L(p<0.02). Conclusions. Our study strongly demonstrates that the NBS1 gene polymorphism (rs1805794 SNP_G>C) has a protective role against toxicity, reducing the incidence of severe grade episodes. High expression of both BRCA1 and BRCA2 genes in leukemic cells seems to be associated with a higher incidence of severe toxicity. Finally, high expression of BRCA1 and BRCA2 genes in the host cells, at remission, is strongly correlated with a higher risk of relapse. Although this study has been performed with an adequate number of children with B-ALL, it is mandatory to perform a prospective project with a larger population.

Phosphorylated Hsp27 promotes adriamycin resistance in breast cancer cells through regulating dual phosphorylation of c-Myc

Chemotherapy resistance of breast cancer cells is one of the major factors affecting patient survival rate. Heat shock protein 27 (Hsp27) is a member of the small heat shock protein family that has been reported to be associated with chemotherapy resistance in tumor cells, but the exact mechanism is not fully understood. Here, we explored the regulation of Hsp27 in adriamycin-resistant pathological conditions of breast cancer in vitro and in vivo. We found that overexpression of Hsp27 in MCF-7 breast cancer cells reversed DNA damage induced by adriamycin, and thereby reduced subsequent cell apoptosis. Non-phosphorylated Hsp27 accelerated ubiquitin-mediated degradation of c-Myc under normal physiological conditions. After stimulation with adriamycin, Hsp27 was phosphorylated and translocated from the cytoplasm into the nucleus, where phosphorylated Hsp27 upregulated c-Myc and Nijmegen breakage syndrome 1 (NBS1) protein levels thus leading to ATM activation. We further showed that phosphorylated Hsp27 promoted c-Myc nuclear import and stabilization by regulating T58/S62 phosphorylation of c-Myc through a protein phosphatase 2A (PP2A)-dependent mechanism. Collectively, the data presented in this study demonstrate that Hsp27, in its phosphorylation state, plays a critical role in adriamycin-resistant pathological conditions of breast cancer cells.

Simultaneous Nbs1 and p53 inactivation in neural progenitors triggers high-grade gliomas.

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder caused by hypomorphic mutations of NBS1. NBS1 is a member of the MRE11-RAD50-NBS1 (MRN) complex that binds to DNA double-strand breaks and activates the DNA damage response (DDR). Nbs1 inactivation in neural progenitor cells leads to microcephaly and premature death. Interestingly, p53 homozygous deletion rescues the NBS1-deficient phenotype allowing long-term survival. The objective of this work was to determine whether simultaneous inactivation of Nbs1 and p53 in neural progenitors triggered brain tumorigenesis and if so in which category this tumour could be classified. We generated a mouse model with simultaneous genetic inactivation of Nbs1 and p53 in embryonic neural stem cells and analysed the arising tumours with in-depth molecular analyses including immunohistochemistry, array comparative genomic hybridisation (aCGH), whole exome-sequencing and RNA-sequencing. NBS1/P53-deficient mice develop high-grade gliomas (HGG) arising in the olfactory bulbs and in the cortex along the rostral migratory stream. In-depth molecular analyses using immunohistochemistry, aCGH, whole exome-sequencing and RNA-sequencing revealed striking similarities to paediatric human HGG with shared features with radiation-induced gliomas (RIGs). Our findings show that concomitant inactivation of Nbs1 and p53 in mice promotes HGG with RIG features. This model could be useful for preclinical studies to improve the prognosis of these deadly tumours, but it also highlights the singularity of NBS1 among the other DNA damage response proteins in the aetiology of brain tumours.

Dissection of DNA damage and repair pathways in live cells by femtosecond laser microirradiation and free-electron modeling

Understanding and predicting the outcome of the interaction of light with DNA has a significant impact on the study of DNA repair and radiotherapy. We report on a combination of femtosecond pulsed laser microirradiation at different wavelengths, quantitative imaging, and numerical modeling that yields a comprehensive picture of photon-mediated and free-electron-mediated DNA damage pathways in live cells. Laser irradiation was performed under highly standardized conditions at four wavelengths between 515 nm and 1,030 nm, enabling to study two-photon photochemical and free-electron-mediated DNA damage in situ. We quantitatively assessed cyclobutane pyrimidine dimer (CPD) and γH2AX-specific immunofluorescence signals to calibrate the damage threshold dose at these wavelengths and performed a comparative analysis of the recruitment of DNA repair factors xeroderma pigmentosum complementation group C (XPC) and Nijmegen breakage syndrome 1 (Nbs1). Our results show that two-photon-induced photochemical CPD generation dominates at 515 nm, while electron-mediated damage dominates at wavelengths ≥620 nm. The recruitment analysis revealed a cross talk between nucleotide excision and homologous recombination DNA repair pathways at 515 nm. Numerical simulations predicted electron densities and electron energy spectra, which govern the yield functions of a variety of direct electron-mediated DNA damage pathways and of indirect damage by •OH radicals resulting from laser and electron interactions with water. Combining these data with information on free electron-DNA interactions gained in artificial systems, we provide a conceptual framework for the interpretation of the wavelength dependence of laser-induced DNA damage that may guide the selection of irradiation parameters in studies and applications that require the selective induction of DNA lesions.

A rare case of primary gastric Hodgkin lymphoma in an adolescent with Nijmegen breakage syndrome

BackgroundNijmegen Breakage Syndrome (NBS) is a rare autosomal recessive DNA repair disorder that increases risk of hematological malignancy. Primary gastric malignancies are exceedingly rare in pediatric patients and not typically high on the differential of abdominal pain.Case presentationA 14-year-old male with NBS presented with persistent abdominal pain and was diagnosed with primary Hodgkin disease of the stomach.ConclusionsIn pediatric patients with predisposition to malignancies, such as those with underlying chromosome instability disorders, all symptoms must be carefully considered.

Clinical and laboratory diversity of diffuse large B-cell lymphomas in children with Nijmegen breakage syndrome.

Not available.