The MRE11, RAD50, and NBN genes encode for the nuclear MRN protein complex, which senses the DNA double strand breaks and initiates the DNA repair. The MRN complex also participates in the activation of ATM kinase, which coordinates DNA repair with the p53-dependent cell cycle checkpoint arrest. Carriers of homozygous germline pathogenic variants in the MRN complex genes or compound heterozygotes develop phenotypically distinct rare autosomal recessive syndromes characterized by chromosomal instability and neurological symptoms. Heterozygous germline alterations in the MRN complex genes have been associated with a poorly-specified predisposition to various cancer types. Somatic alterations in the MRN complex genes may represent valuable predictive and prognostic biomarkers in cancer patients. MRN complex genes have been targeted in several next-generation sequencing panels for cancer and neurological disorders, but interpretation of the identified alterations is challenging due to the complexity of MRN complex function in the DNA damage response. In this review, we outline the structural characteristics of the MRE11, RAD50 and NBN proteins, the assembly and functions of the MRN complex from the perspective of clinical interpretation of germline and somatic alterations in the MRE11, RAD50 and NBN genes.

• Klíčová slova
• ATLD, DNA repair, MRE11, NBN, NBS, NBSLD, NGS, RAD50, TP53, hereditary cancer syndromes, variant interpretation,
• MeSH
• ATM protein genetika   metabolismus   MeSH
• DNA vazebné proteiny genetika   metabolismus   MeSH
• enzymy opravy DNA genetika   metabolismus   MeSH
• homologní protein MRE11 genetika   metabolismus   MeSH
• hydrolasy působící na anhydridy kyselin genetika   metabolismus   MeSH
• jaderné proteiny genetika   metabolismus   MeSH
• lidé MeSH
• nádorové supresorové proteiny * genetika   MeSH
• oprava DNA genetika   MeSH
• proteiny buněčného cyklu * metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• ATM protein MeSH
• DNA vazebné proteiny MeSH
• enzymy opravy DNA MeSH
• homologní protein MRE11 MeSH
• hydrolasy působící na anhydridy kyselin MeSH
• jaderné proteiny MeSH
• nádorové supresorové proteiny * MeSH
• NBN protein, human MeSH Prohlížeč
• proteiny buněčného cyklu * MeSH
• RAD50 protein, human MeSH Prohlížeč

BACKGROUND: Nijmegen breakage syndrome (NBS) is an autosomal-recessive chromosome instability disorder characterized by, among others, hypersensitivity to X-irradiation and an exceptionally high risk for lymphoid malignancy. The vast majority of NBS patients is homozygous for a common Slavic founder mutation, c.657del5, of the NBN gene, which is involved in the repair of DNA double-strand breaks (DSBs). The founder mutation also predisposes heterozygous carriers to cancer, apparently however, with a higher risk in the Czech Republic/Slovakia (CS) than in Poland. AIM: To examine whether the age of cancer manifestation and cancer death of NBN homozygotes is different between probands from CS and Poland. METHODS: The study is restricted to probands born until 1989, before replacement of the communist regime by a democratic system in CS and Poland, and a substantial transition of the health care systems. Moreover, all patients were recruited without knowledge of their genetic status since the NBN gene was not identified until 1998. RESULTS: Here, we show that cancer manifestation of NBN homozygotes is at a significantly earlier age in probands from CS than from Poland. This is explained by the difference in natural and medical radiation exposure, though within the permissible dosage. CONCLUSION: It is reasonable to assume that this finding also sheds light on the higher cancer risk of NBN heterozygotes in CS than in Poland. This has implications for genetic counseling and individualized medicine also of probands with other DNA repair defects.

• Klíčová slova
• NBS, age of cancer manifestation, cancer risk of heterozygotes, environmental and medical exposure to ionizing radiation,
• MeSH
• heterozygot MeSH
• jaderné proteiny genetika   MeSH
• lidé MeSH
• mutace MeSH
• nádory * MeSH
• proteiny buněčného cyklu genetika   MeSH
• syndrom Nijmegen breakage * genetika   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• jaderné proteiny MeSH
• NBN protein, human MeSH Prohlížeč
• proteiny buněčného cyklu MeSH

Cancer therapy failure is a fundamental challenge in cancer treatment. One of the most common reasons for therapy failure is the development of acquired resistance of cancer cells. DNA-damaging agents are frequently used in first-line chemotherapy regimens and DNA damage response, and DNA repair pathways are significantly involved in the mechanisms of chemoresistance. MRE11, a part of the MRN complex involved in double-strand break (DSB) repair, is connected to colorectal cancer (CRC) patients' prognosis. Our previous results showed that single-nucleotide polymorphisms (SNPs) in the 3' untranslated region (3'UTR) microRNA (miRNA) binding sites of MRE11 gene are associated with decreased cancer risk but with shorter survival of CRC patients, which implies the role of miRNA regulation in CRC. The therapy of colorectal cancer utilizes oxaliplatin (oxalato(trans-l-1,2-diaminocyclohexane)platinum), which is often compromised by chemoresistance development. There is, therefore, a crucial clinical need to understand the cellular processes associated with drug resistance and improve treatment responses by applying efficient combination therapies. The main aim of this study was to investigate the effect of miRNAs on the oxaliplatin therapy response of CRC patients. By the in silico analysis, miR-140 was predicted to target MRE11 and modulate CRC prognosis. The lower expression of miR-140 was associated with the metastatic phenotype (p < 0.05) and poor progression-free survival (odds ratio (OR) = 0.4, p < 0.05). In the in vitro analysis, we used miRNA mimics to increase the level of miR-140 in the CRC cell line. This resulted in decreased proliferation of CRC cells (p < 0.05). Increased levels of miR-140 also led to increased sensitivity of cancer cells to oxaliplatin (p < 0.05) and to the accumulation of DNA damage. Our results, both in vitro and in vivo, suggest that miR-140 may act as a tumor suppressor and plays an important role in DSB DNA repair and, consequently, CRC therapy response.

• Klíčová slova
• DNA damage, DNA repair, MRE11, colorecal cancer, miR-140, miRNA, oxaliplatin, therapy response,
• Publikační typ
• časopisecké články MeSH

The MRN (MRE11-RAD50-NBS1) complex is essential for repair of DNA double-strand breaks and stalled replication forks. Mutations of the MRN complex subunit MRE11 cause the hereditary cancer-susceptibility disease ataxia-telangiectasia-like disorder (ATLD). Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689. Conversely, the PIH1D1 phospho-binding domain PIH-N is required for association with MRE11 phosphorylated by CK2. Consistent with these findings, depletion of PIH1D1 resulted in MRE11 destabilization and affected DNA-damage repair processes dependent on MRE11. Additionally, mutations of serines 688/689, which abolish PIH1D1 binding, also resulted in decreased MRE11 stability. As depletion of R2TP frequently leads to instability of its substrates and as truncation mutation of MRE11 lacking serines 688/689 leads to decreased levels of the MRN complex both in ATLD patients and an ATLD mouse model, our results suggest that the MRN complex is a novel R2TP complex substrate and that their interaction is regulated by CK2 phosphorylation.

• MeSH
• ATM protein metabolismus   MeSH
• buněčné jádro metabolismus   MeSH
• DNA vazebné proteiny metabolismus   MeSH
• enzymy opravy DNA metabolismus   MeSH
• fosforylace fyziologie   MeSH
• jaderné proteiny metabolismus   MeSH
• kaseinkinasa II metabolismus   MeSH
• lidé MeSH
• mutace fyziologie   MeSH
• myši MeSH
• oprava DNA fyziologie   MeSH
• poškození DNA fyziologie   MeSH
• proteiny regulující apoptózu metabolismus   MeSH
• proteiny teplotního šoku metabolismus   MeSH
• ribonukleoproteiny malé jadérkové metabolismus   MeSH
• RNA-polymerasa II metabolismus   MeSH
• serin metabolismus   MeSH
• teleangiektatická ataxie metabolismus   MeSH
• TOR serin-threoninkinasy metabolismus   MeSH
• vazba proteinů fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ATM protein MeSH
• DNA vazebné proteiny MeSH
• enzymy opravy DNA MeSH
• jaderné proteiny MeSH
• kaseinkinasa II MeSH
• proteiny regulující apoptózu MeSH
• proteiny teplotního šoku MeSH
• ribonukleoproteiny malé jadérkové MeSH
• RNA-polymerasa II MeSH
• serin MeSH
• TOR serin-threoninkinasy MeSH

The vast majority of patients with Nijmegen Breakage Syndrome (NBS) are of Slavic origin and carry a deleterious deletion (c.657del5; rs587776650) in the NBN gene on chromosome 8q21. This mutation is essentially confined to Slavic populations and may thus be considered a Slavic founder mutation. Notably, not a single parenthood of a homozygous c.657del5 carrier has been reported to date, while heterozygous carriers do reproduce but have an increased cancer risk. These observations seem to conflict with the considerable carrier frequency of c.657del5 of 0.5% to 1% as observed in different Slavic populations because deleterious mutations would be eliminated quite rapidly by purifying selection. Therefore, we propose that heterozygous c.657del5 carriers have increased reproductive success, i.e., that the mutation confers heterozygote advantage. In fact, in our cohort study of the reproductive history of 24 NBS pedigrees from the Czech Republic, we observed that female carriers gave birth to more children on average than female non-carriers, while no such reproductive differences were observed for males. We also estimate that c.657del5 likely occurred less than 300 generations ago, thus supporting the view that the original mutation predated the historic split and subsequent spread of the 'Slavic people'. We surmise that the higher fertility of female c.657del5 carriers reflects a lower miscarriage rate in these women, thereby reflecting the role of the NBN gene product, nibrin, in the repair of DNA double strand breaks and their processing in immune gene rearrangements, telomere maintenance, and meiotic recombination, akin to the previously described role of the DNA repair genes BRCA1 and BRCA2.

• MeSH
• detekce genetických nosičů MeSH
• dospělí MeSH
• efekt zakladatele * MeSH
• haplotypy MeSH
• jaderné proteiny genetika   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace * MeSH
• oprava DNA MeSH
• poškození DNA MeSH
• proteiny buněčného cyklu genetika   MeSH
• rozmnožování genetika   MeSH
• syndrom Nijmegen breakage etnologie   genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Slovenská republika MeSH
• Názvy látek
• jaderné proteiny MeSH
• NBN protein, human MeSH Prohlížeč
• proteiny buněčného cyklu MeSH

Telomeres, as physical ends of linear chromosomes, are targets of a number of specific proteins, including primarily telomerase reverse transcriptase. Access of proteins to the telomere may be affected by a number of diverse factors, e.g., protein interaction partners, local DNA or chromatin structures, subcellular localization/trafficking, or simply protein modification. Knowledge of composition of the functional nucleoprotein complex of plant telomeres is only fragmentary. Moreover, the plant telomeric repeat binding proteins that were characterized recently appear to also be involved in non-telomeric processes, e.g., ribosome biogenesis. This interesting finding was not totally unexpected since non-telomeric functions of yeast or animal telomeric proteins, as well as of telomerase subunits, have been reported for almost a decade. Here we summarize known facts about the architecture of plant telomeres and compare them with the well-described composition of telomeres in other organisms.

• Klíčová slova
• plant, shelterin, telomerase, telomere, telomeric proteins, telomeric repeat binding (TRB),
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Telomeres, as elaborate nucleo-protein complexes, ensure chromosomal stability. When impaired, the ends of linear chromosomes can be recognised by cellular repair mechanisms as double-strand DNA breaks and can be healed by non-homologous-end-joining activities to produce dicentric chromosomes. During cell divisions, particularly during anaphase, dicentrics can break, thus producing naked chromosome tips susceptible to additional unwanted chromosome fusion. Many telomere-building protein complexes are associated with telomeres to ensure their proper capping function. It has been found however, that a number of repair complexes also contribute to telomere stability. RESULTS: We used Arabidopsis thaliana to study the possible functions of the DNA repair subunit, NBS1, in telomere homeostasis using knockout nbs1 mutants. The results showed that although NBS1-deficient plants were viable, lacked any sign of developmental aberration and produced fertile seeds through many generations upon self-fertilisation, plants also missing the functional telomerase (double mutants), rapidly, within three generations, displayed severe developmental defects. Cytogenetic inspection of cycling somatic cells revealed a very early onset of massive genome instability. Molecular methods used for examining the length of telomeres in double homozygous mutants detected much faster telomere shortening than in plants deficient in telomerase gene alone. CONCLUSIONS: Our findings suggest that NBS1 acts in concert with telomerase and plays a profound role in plant telomere renewal.

• MeSH
• anafáze MeSH
• Arabidopsis cytologie   enzymologie   genetika   růst a vývoj   MeSH
• chromozomální nestabilita MeSH
• chromozomy rostlin genetika   metabolismus   MeSH
• cytogenetické vyšetření MeSH
• DNA vazebné proteiny genetika   metabolismus   MeSH
• homeostáza telomer MeSH
• homologní protein MRE11 MeSH
• hybridizace in situ fluorescenční MeSH
• jaderné proteiny genetika   metabolismus   MeSH
• klíčení MeSH
• květy cytologie   genetika   metabolismus   MeSH
• mapování interakce mezi proteiny MeSH
• meióza MeSH
• oprava DNA MeSH
• proteiny buněčného cyklu genetika   metabolismus   MeSH
• proteiny huseníčku genetika   metabolismus   MeSH
• rostlinné buňky enzymologie   metabolismus   MeSH
• samooplození MeSH
• semena rostlinná genetika   růst a vývoj   metabolismus   MeSH
• telomerasa genetika   metabolismus   MeSH
• telomery genetika   metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA vazebné proteiny MeSH
• homologní protein MRE11 MeSH
• jaderné proteiny MeSH
• Mre11 protein, Arabidopsis MeSH Prohlížeč
• proteiny buněčného cyklu MeSH
• proteiny huseníčku MeSH
• rad50 protein, Arabidopsis MeSH Prohlížeč
• telomerasa MeSH
• TERT protein, Arabidopsis MeSH Prohlížeč