We analyzed the FRAXAC2 and DXS548 microsatellites in normal and fragile X chromosomes from Sweden and the Czech Republic in order to investigate a possible founder effect for chromosomes carrying a fragile X mutation. We report a much stronger linkage disequilibrium between the marker haplotypes and the disease in Swedish fragile X chromosomes than in Czech and most other previously studied Caucasian populations. Two haplotypes accounted for 64% of Swedish fragile X chromosomes and for only 14% of normal chromosomes. Neither of these two haplotypes was found in Czech chromosomes, but the most common Swedish fragile X haplotype is the same as that reported to be predominant in Finnish fragile X patients. Linkage disequilibrium was observed in the Czech fragile X chromosomes but the haplotypes were more diverse and similar to those observed in other Caucasian populations. The most prevalent Swedish fragile X haplotype was traced back from affected males to common ancestors in the early 18th century. This indicates an apparently silent segregation of fragile X alleles through up to nine generations. The geographical distribution of the two major at-risk haplotypes in Sweden suggests that they were present among early settlers in different parts of the country.

• MeSH
• Gene Frequency MeSH
• Haplotypes MeSH
• Humans MeSH
• Molecular Epidemiology MeSH
• Genetics, Population * MeSH
• Pedigree MeSH
• Chi-Square Distribution MeSH
• DNA, Satellite analysis   MeSH
• Fragile X Syndrome epidemiology   genetics   MeSH
• Linkage Disequilibrium MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Geographicals
• Czech Republic MeSH
• Sweden MeSH

The MUS81-EME1 endonuclease cleaves late replication intermediates at common fragile sites (CFSs) during early mitosis to trigger DNA-repair synthesis that ensures faithful chromosome segregation. Here, we show that these DNA transactions are promoted by RECQ5 DNA helicase in a manner dependent on its Ser727 phosphorylation by CDK1. Upon replication stress, RECQ5 associates with CFSs in early mitosis through its physical interaction with MUS81 and promotes MUS81-dependent mitotic DNA synthesis. RECQ5 depletion or mutational inactivation of its ATP-binding site, RAD51-interacting domain, or phosphorylation site causes excessive binding of RAD51 to CFS loci and impairs CFS expression. This leads to defective chromosome segregation and accumulation of CFS-associated DNA damage in G1 cells. Biochemically, RECQ5 alleviates the inhibitory effect of RAD51 on 3'-flap DNA cleavage by MUS81-EME1 through its RAD51 filament disruption activity. These data suggest that RECQ5 removes RAD51 filaments stabilizing stalled replication forks at CFSs and hence facilitates CFS cleavage by MUS81-EME1.

• MeSH
• Time Factors MeSH
• Chromosomal Instability MeSH
• Cyclin-Dependent Kinases metabolism   MeSH
• DNA-Binding Proteins genetics   metabolism   MeSH
• DNA biosynthesis   genetics   MeSH
• Endodeoxyribonucleases metabolism   MeSH
• Endonucleases genetics   metabolism   MeSH
• Phosphorylation MeSH
• Chromosome Fragile Sites * MeSH
• HEK293 Cells MeSH
• HeLa Cells MeSH
• RecQ Helicases genetics   metabolism   MeSH
• Humans MeSH
• Mitosis * MeSH
• DNA Repair * MeSH
• DNA Damage MeSH
• Rad51 Recombinase metabolism   MeSH
• Replication Origin * MeSH
• RNA Interference MeSH
• Chromosome Segregation MeSH
• Transfection MeSH
• Protein Binding MeSH
• Binding Sites MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Replication stress (RS) fuels genomic instability and cancer development and may contribute to aging, raising the need to identify factors involved in cellular responses to such stress. Here, we present a strategy for identification of factors affecting the maintenance of common fragile sites (CFSs), which are genomic loci that are particularly sensitive to RS and suffer from increased breakage and rearrangements in tumors. A DNA probe designed to match the high flexibility island sequence typical for the commonly expressed CFS (FRA16D) was used as specific DNA affinity bait. Proteins significantly enriched at the FRA16D fragment under normal and replication stress conditions were identified using stable isotope labeling of amino acids in cell culture-based quantitative mass spectrometry. The identified proteins interacting with the FRA16D fragment included some known CFS stabilizers, thereby validating this screening approach. Among the hits from our screen so far not implicated in CFS maintenance, we chose Xeroderma pigmentosum protein group C (XPC) for further characterization. XPC is a key factor in the DNA repair pathway known as global genomic nucleotide excision repair (GG-NER), a mechanism whose several components were enriched at the FRA16D fragment in our screen. Functional experiments revealed defective checkpoint signaling and escape of DNA replication intermediates into mitosis and the next generation of XPC-depleted cells exposed to RS. Overall, our results provide insights into an unexpected biological role of XPC in response to replication stress and document the power of proteomics-based screening strategies to elucidate mechanisms of pathophysiological significance.

• MeSH
• Chromatography, Affinity MeSH
• DNA-Binding Proteins physiology   MeSH
• Chromosome Fragile Sites MeSH
• Cell Cycle Checkpoints MeSH
• Humans MeSH
• DNA Repair physiology   MeSH
• Proteomics methods   MeSH
• DNA Replication physiology   MeSH
• Xeroderma Pigmentosum MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The semiconservative replication of telomeres is facilitated by the shelterin component TRF1. Without TRF1, replication forks stall in the telomeric repeats, leading to ATR kinase signaling upon S-phase progression, fragile metaphase telomeres that resemble the common fragile sites (CFSs), and the association of sister telomeres. In contrast, TRF1 does not contribute significantly to the end protection functions of shelterin. We addressed the mechanism of TRF1 action using mouse conditional knockouts of BLM, TRF1, TPP1, and Rap1 in combination with expression of TRF1 and TIN2 mutants. The data establish that TRF1 binds BLM to facilitate lagging but not leading strand telomeric DNA synthesis. As the template for lagging strand telomeric DNA synthesis is the TTAGGG repeat strand, TRF1-bound BLM is likely required to remove secondary structures formed by these sequences. In addition, the data establish that TRF1 deploys TIN2 and the TPP1/POT1 heterodimers in shelterin to prevent ATR during telomere replication and repress the accompanying sister telomere associations. Thus, TRF1 uses two distinct mechanisms to promote replication of telomeric DNA and circumvent the consequences of replication stress. These data are relevant to the expression of CFSs and provide insights into TIN2, which is compromised in dyskeratosis congenita (DC) and related disorders.

• MeSH
• Enzyme Activation MeSH
• Aminopeptidases genetics   metabolism   MeSH
• Ataxia Telangiectasia Mutated Proteins metabolism   MeSH
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases genetics   metabolism   MeSH
• DNA-Binding Proteins metabolism   MeSH
• Gene Knockout Techniques MeSH
• RecQ Helicases genetics   metabolism   MeSH
• Cells, Cultured MeSH
• Microsatellite Repeats genetics   MeSH
• Mutation MeSH
• Telomeric Repeat Binding Protein 1 genetics   metabolism   MeSH
• Telomere-Binding Proteins genetics   metabolism   MeSH
• DNA Replication genetics   MeSH
• Serine Proteases genetics   metabolism   MeSH
• Signal Transduction MeSH
• Telomere genetics   MeSH
• Protein Binding MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

The SLX4 tumor suppressor is a scaffold that plays a pivotal role in several aspects of genome protection, including homologous recombination, interstrand DNA crosslink repair and the maintenance of common fragile sites and telomeres. Here, we unravel an unexpected direct interaction between SLX4 and the DNA helicase RTEL1, which, until now, were viewed as having independent and antagonistic functions. We identify cancer and Hoyeraal-Hreidarsson syndrome-associated mutations in SLX4 and RTEL1, respectively, that abolish SLX4-RTEL1 complex formation. We show that both proteins are recruited to nascent DNA, tightly co-localize with active RNA pol II, and that SLX4, in complex with RTEL1, promotes FANCD2/RNA pol II co-localization. Importantly, disrupting the SLX4-RTEL1 interaction leads to DNA replication defects in unstressed cells, which are rescued by inhibiting transcription. Our data demonstrate that SLX4 and RTEL1 interact to prevent replication-transcription conflicts and provide evidence that this is independent of the nuclease scaffold function of SLX4.

• MeSH
• DNA Helicases genetics   metabolism   MeSH
• Dyskeratosis Congenita genetics   MeSH
• Transcription, Genetic * MeSH
• HeLa Cells MeSH
• Humans MeSH
• Intellectual Disability genetics   MeSH
• Microcephaly genetics   MeSH
• Fanconi Anemia Complementation Group D2 Protein genetics   metabolism   MeSH
• Recombinases genetics   metabolism   MeSH
• DNA Replication * MeSH
• Fetal Growth Retardation genetics   MeSH
• Germ-Line Mutation MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: WWOX (WW domain-containing oxidoreductase) gene, located on chromosome 16q 23.3-24.1 in the region recognized as the common fragile site FRA16D is considered to be a tumor suppressor gene involved in various cancers: breast, ovarian, prostate, esophageal, lung, pancreatic, gastric and hepatic. The aim of this study was to describe (i) putative protein interactions of WWOX (ii) the molecular mechanisms of tumor suppressor activity (iii) present an overview of WWOX in relation to nervous system and breast, prostate and ovarian cancers. METHODS AND RESULTS: WWOX expression is up-regulated in endocrine organs indicating its importance in these tissues. In many cancers WWOX expression is down-regulated and low WWOX expression is related to poor prognosis. CONCLUSION: All the evidence suggest that WWOX can be considered as a new tumor suppressor gene and target for gene therapy due to the association of high WWOX expression with improved disease free survival.

• MeSH
• Gene Expression MeSH
• Humans MeSH
• Tumor Suppressor Proteins genetics   MeSH
• Prostatic Neoplasms genetics   MeSH
• Breast Neoplasms genetics   MeSH
• Ovarian Neoplasms genetics   MeSH
• Neoplasms genetics   MeSH
• Oxidoreductases genetics   MeSH
• Genes, Tumor Suppressor MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

PURPOSE: Deficiency of dihydropyrimidine dehydrogenase (DPD) has been associated with severe fluoropyrimidines (FP) toxicity. Mutations in DPD-coding gene (DPYD) were shown to increase the risk of severe toxicity in FP-treated cancer patients. However, the majority of DPYD alterations characterized in these patients has been considered as polymorphisms and known deleterious mutations are rare and present in only limited subgroup of patients with high toxicity. Recently, the common fragile site FRA1E was mapped within DPYD locus but intragenic rearrangements in DPYD gene were not studied so far. METHODS: We performed the analysis of intragenic rearrangements of DPYD using multiplex ligation-dependent probe amplification in 68 patients with high-grade gastrointestinal and/or hematological toxicity developed at the beginning of FP treatment. RESULTS: We did not detect any deletion/duplication of one or more DPYD exons in analyzed patients. CONCLUSIONS: We assume that rearrangements in DPYD gene play insignificant role in the development of serious FP-related toxicity.

• MeSH
• Dihydrouracil Dehydrogenase (NADP) genetics   MeSH
• Adult MeSH
• Exons MeSH
• Fluorouracil adverse effects   therapeutic use   MeSH
• Gastrointestinal Diseases chemically induced   MeSH
• Hematologic Diseases chemically induced   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation MeSH
• Neoplasms drug therapy   genetics   MeSH
• Polymorphism, Genetic MeSH
• Antimetabolites, Antineoplastic adverse effects   therapeutic use   MeSH
• Pyrimidines adverse effects   therapeutic use   MeSH
• Aged MeSH
• Severity of Illness Index MeSH
• Nucleic Acid Amplification Techniques methods   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH

Problematika príčin vzniku intrakraniálneho krvácania u predčasne narodených detí je stále aktuálna. Príčiny vzniku sú multifaktoriálne. Pri patogenéze intraventrikulámeho krvácania (IVH) zohráva úlohu krehká subependymálna kapilárna sieť v oblasti germinálnej matrix, pričom dochádza k vzájomnej kombinácii intravaskulámych, vaskulámych a extravaskulámych faktorov. Klinické priznaky môžu byť "katastrofická', "saltatóme'' a najčastejšie klinicky " nemé ", kedy sa príznaky ľahko dajú prehliadnuť. Prevencia vzniku WH spočíva v predchádzaní predčasným pôrodom (zlepšením starostlivosti o rizikové gravidity), v podávaní kortikoidov matke, v dôslednej liečbe infekcií u matky najmä pri predčasnom odtoku plodovej vody), centralizácii predčasných pôrodov v perinatálnych centrách, v optimálnom monitorovaní plodov (pred a počas pôrodu), v šetrnom vedení pôrodu, adekvátnom primárnom ošetrení (rýchlej kardiopulmonáhiej stabilizácii, prevencii hypoxic, acidózy, hypotermie) a v precíznom monitorovaní po narodení. Len dôkladné pochopenie patomechanizmu IVH nám môže pomôcť pri prevencii vzniku krvácania, v dôsledku ktorého často vzniká trvalé postihnutie predčasne narodených detí.

Prematurity is the most important risk factor for intracranial hemorrhage (ICH). ICH most commonly emanates from the germinal matrix with a fragile vascular area located between the head of caudate nucleus and thalamus. The etiology seems to be multifactorial - often resulted from the combination of intravascular, vascular and extravascular factors. Three basic clinical syndromes accompany ICH - a catastrophic deterioration, a saltatory deterioration and clinically silent syndrome, which is the most common of all. The prevention of ICH is focused on advancing gestational age, antenatal corticosteroid therapy, antenatal antibacterial therapy, especially in the presence of rupture of membranes, centralization of premature labor in perinatal centers, optimal fetal monitoring (before and during the labor), optimal mode of delivery, perfect cardiopulmonary stabilization after birth and precise postnatal monitoring of the premature newborn. Good understanding of ICH pathophysiology in premature neonates will help us in prevention of ICH in order to eliminate severe handicap in this group of infants.

• MeSH
• Child MeSH
• Ethamsylate therapeutic use   MeSH
• Indomethacin therapeutic use   MeSH
• Intracranial Hemorrhages etiology   pathology   therapy   MeSH
• Infant MeSH
• Humans MeSH
• Infant, Premature, Diseases MeSH
• Infant, Newborn MeSH
• Preventive Medicine MeSH
• Resuscitation MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Infant, Newborn MeSH
• Publication type
• Review MeSH

PURPOSE OF THE STUDY To evaluate a possible association between hip fracture and statin use. MATERIAL AND METHODS In this case-control study we compared the use of statins between two groups of 210 patients: the first group (case group) included patients hospitalized for hip fractures while the second group (control group) included patients who did not suffer femur bone injuries. The two groups were matched for age, sex, year of hospitalization and possible confounding factors. Inside the group of cases, we also evaluated the differences in terms of fracture type, presence of previous fragility fracture and mortality between statin users and non-users. RESULTS The use of statins was most common among patients without previous fractures (OR=0.54; 95% CI=0.33-0.89; p=0.0138), especially in older patients (OR=0.40; 95% CI=0.22-0.76). We did not find any significant difference in statin intake between men and women in the control group. In the case group, those who did not use statins were more likely to undergo a medial hip fracture (28.5% vs 16.1%). Patients from case group also presented a greater mortality (27.9% vs 19.35%) and an higher percentage of previous hip fractures (20.11% vs 9.7%). However, they didn't presented a significant higher rate of fragility fractures in other sites. DISCUSSION AND CONCLUSIONS Our study suggests a reduced hip fracture risk, especially in cases aged 80 or more, a different fracture pattern (lower percentage of medial fractures) and a reduced mortality at 9 months in patients treated with HMG-CoA reductase inhibitors, confirming the previous evidences reported in literature. Key words: statin, hip fractures, fracture risk, osteoporosis.

• MeSH
• Hip Fractures * epidemiology   prevention & control   MeSH
• Bone and Bones MeSH
• Humans MeSH
• Osteoporosis * MeSH
• Aged MeSH
• Hydroxymethylglutaryl-CoA Reductase Inhibitors * adverse effects   MeSH
• Case-Control Studies MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

• MeSH
• Breast Neoplasms MeSH
• Therapeutics MeSH
• Publication type
• Collected Work MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• onkologie
• gynekologie a porodnictví
• terapie