SLX4 interacts with RTEL1 to prevent transcription-mediated DNA replication perturbations.

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.

Publisher Correction: SLX4 interacts with RTEL1 to prevent transcription-mediated DNA replication perturbations.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Author Correction: SLX4 interacts with RTEL1 to prevent transcription-mediated DNA replication perturbations.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

[Ultrasonic geometry of synthetic endoprostheses after transabdominal preperitoneal hernioplasty of inguinal hernias]. / Ul'trazvukovaia geometriia sinteticheskikh éndoprotezov posle transabdominal'noi preperitoneal'noi gernioplastiki pakhovoi gryzhi.

OBJECTIVE: To assess position of mesh endoprosthesis in retroperitoneal space after TARR hernioplasty using ultrasound in early and long-term postoperative period. MATERIAL AND METHODS: There were 30 patients with inguinal hernias after TARR procedure. Standard technology of laparoscopic transabdominal preperitoneal hernioplasty was used in all patients. In all cases, a large-pore monofilament polypropylene mesh 10x15 cm was used. Control examination and ultrasound of the mesh implant were performed the next day, in 1, 3, 6, 12 months after surgery. Correct position of the implant was determined by its placement at the level of pubic bone with complete overlap of posterior wall of the inguinal canal and inner ring. RESULTS: US-image of the implant is present in two geometric forms - linear and sinusoid. The shape of prosthesis varies depending on postoperative period and the use of fixing elements. Thus, sinusoidal shape of prosthesis was observed in patients without fixation of prosthesis the next day and in 1 month after TARR. Geometry of the implant acquired the form of a straight line after 3 months and became almost a straight line in 12 months after surgery. Linear shape of prosthesis in early postoperative period was found after intraoperative fixation of endoprosthesis. Sinusoidal shape is noted after 3 months. Ultrasonic pattern of endoprosthesis looked as a thin hyperechoic band with thickness of 1.2-3.9 mm. Mean thickness of prosthesis was 2.2±0.1 mm the next day after surgery, 2.8±0.2 mm after 1 month and 1.6±0.05 mm after 12 months. CONCLUSION: Geometry of synthetic implants after TARR hernioplasty undergoes significant changes and depends on duration of postoperative period and fixation of the prosthesis.

Single nucleotide polymorphisms in chum salmon (Oncorhynchus keta) mitochondrial DNA derived from restriction site haplotype information.

Single nucleotide polymorphisms (SNPs) are useful genetic markers for the management and conservation of commercially important species such as salmon. Informative markers can be derived from data obtained for other purposes. We used restriction endonuclease data from earlier work to identify potentially useful restriction sites in chum salmon (Oncorhynchus keta). With the aid of a newly generated complete mitochondrial DNA sequence (accession number AP010773), we identified the SNP responsible for each restriction site variant, designed rapid genotyping assays, and surveyed the SNPs in more than 400 individuals. The restriction site analysis and the SNP genotyping assays were almost perfectly concordant. Some reasons for the non-concordance were identified and discussed.

In search of candidate genes critically expressed in the human endometrium during the window of implantation.

BACKGROUND: In this prospective randomized blinded clinical trial, we examined gene expression profiles of the human endometrium during the early and mid-luteal phases of the natural cycle. METHODS: An endometrial biopsy was performed on day 16 (LH +3) or on day 21 (LH +8), followed by RNA extraction and microarray analysis using an Affymetrix HG-U95A microchip. Data analysis was carried out using pairwise multiple group comparison with the significance analysis of microarrays (SAM) software. RESULTS: With a false discovery rate of 0, the analysis revealed that 107 genes were significantly and differently expressed (> or =2-fold) during the early versus the mid-luteal phase of the cycle. Forty-five of these genes have not been previously linked to endometrial receptivity. Validation of the microarray data was accomplished using semiquantitative RT-PCR. We demonstrated the presence of estrogen and progesterone response elements (ERE and PRE) by analysis of the 5'-flanking regions of a subset of differentially regulated genes. CONCLUSIONS: Using a strict bioinformatics approach of microarray data, we demonstrated significant changes in candidate genes during the transition of the early to the mid-luteal phase of the human endometrium that may have functional significance for the opening and maintenance of the window of implantation.

Male germline-specific histones in mouse and man.

In mice and humans, the production of male gametes is a result of a complex multistep process of stem cell differentiation. The final product, the mature spermatozoon, is designed for the safe delivery of a haploid copy of the paternal genetic information to the oocyte in a structural state suitable for zygote formation and embryogenesis. A remarkable structural reorganization of chromosomes in germline cells during mammalian spermatogenesis has been characterized. The most important steps are connected with the recombination events during meiosis and the final packaging of the haploid genome in the genetically inert, compacted nucleus of the sperm. Underlying the changes in chromatin organization is the appearance of testis-specific histones. Although the existence of such histones has been known for decades, their exact functions still are not established. Deciphering of the mouse and human genomes has allowed a more detailed description of the organization and regulation of the testis-specific histone genes. In addition, it has facilitated the discovery of previously unknown proteins. This review summarizes contemporary information on these germline-specific/enriched histones in both the mouse and human and outlines early achievements in the identification of their functions.

Comparative phylogeography of the two pink salmon broodlines: an analysis based on a mitochondrial DNA genealogy.

Over most of their natural northern Pacific Ocean range, pink salmon (Oncorhynchus gorbuscha) spawn in a habitat that was repeatedly and profoundly affected by Pleistocene glacial advances. A strictly two-year life cycle of pink salmon has resulted in two reproductively isolated broodlines, which spawn in alternating years and evolved as temporal replicates of the same species. To study the influence of historical events on phylogeographical and population genetic structure of the two broodlines, we first reconstructed a fine-scale mtDNA haplotype genealogy from a sample of 80 individuals and then determined the geographical distribution of the major genealogical assemblages for 718 individuals sampled from nine Alaskan and eastern Asian even- and nine odd-year pink salmon populations. Analysis of restriction site states in seven polymerase chain reaction (PCR)-amplified mtDNA regions (comprising 97% of the mitochondrial genome) using 13 endonucleases resolved 38 haplotypes, which clustered into five genealogical lineages that differed from 0.065 to 0.225% in net sequence divergence. The lineage sorting between broodlines was incomplete, which suggests a recent common ancestry. Within each lineage, haplotypes exhibited star-like genealogies indicating recent population growth. The depth of the haplotype genealogy is shallow ( approximately 0.5% of nucleotide sequence divergence) and probably reflects repeated decreases in population size due to Pleistocene glacial advances. Nested clade analysis (NCA) of geographical distances showed that the geographical distribution observed for mitochondrial DNA (mtDNA) haplotypes resulted from alternating influences of historical range expansions and episodes of restricted dispersal. Analyses of molecular variance showed weak geographical structuring of mtDNA variation, except for the strong subdivision between Asian and Alaskan populations within the even-year broodline. The genetic similarities observed among and within geographical regions probably originated from postglacial recolonizations from common sources rather than extensive gene flow. The phylogeographical and population genetic structures differ substantally between broodlines. This can be explained by stochastic lineage sorting in glacial refugia and perhaps different recolonization routes in even- and odd-year broodlines.

Assessment of concordance among genealogical reconstructions from various mtDNA segments in three species of Pacific salmon (genus Oncorhynchus).

Seven segments of mitochondrial DNA (mtDNA), comprising 97% of the mitochondrial genome, were amplified by polymerase chain reaction (PCR) and examined for restriction site variation using 13 restriction endonucleases in three species of Pacific salmon: pink (Oncorhynchus gorbuscha), chum (O. keta) and sockeye (O. nerka) salmon. The distribution of variability across the seven mtDNA segments differed substantially among species. Little similarity in the distribution of variable restriction sites was found even between the mitochondrial genomes of the even- and odd-year broodlines of pink salmon. Significantly different levels of nucleotide diversity were detected among three groups of genes: six NADH-dehydrogenase genes had the highest; two rRNA genes had the lowest; and a group that included genes for ATPase and cytochrome oxidase subunits, the cytochrome b gene, and the control region had intermediate levels of nucleotide diversity. Genealogies of mtDNA haplotypes were reconstructed for each species, based on the variation in all mtDNA segments. The contributions of variation within different segments to resolution of the genealogical trees were compared within each species. With the exception of sockeye salmon, restriction site data from different genome segments tended to produce rather different trees (and hence rather different genealogies). In the majority of cases, genealogical information in different segments of mitochondrial genome was additive rather than congruent. This finding has a relevance to phylogeographic studies of other organisms and emphasizes the importance of not relying on a limited segment of the mtDNA genome to derive a phylogeographic structure.