Heterozygous variant as a novel genetic cause of telomere biology disorders.

Premature telomere shortening or telomere instability is associated with a group of rare and heterogeneous diseases collectively known as telomere biology disorders (TBDs). Here we identified two unrelated individuals with clinical manifestations of TBDs and short telomeres associated with the identical monoallelic variant c.767A>G; Y256C in Although the replication protein A2 (RPA2) mutant did not affect ssDNA binding and G-quadruplex-unfolding properties of RPA, the mutation reduced the affinity of RPA2 with the ubiquitin ligase RFWD3 and reduced RPA ubiquitination.

Prospective Cohort Study of a Treatment Strategy for a Combination of the Left Common Iliac Vein Compression Stenosis and Pelvic Venous Insufficiency.

Purpose: To develop a strategy for the iliac vein stenting in patients with a combination of the left common iliac vein (LCIV) compression stenosis and pelvic venous insufficiency (PVI).

Methods: This prospective comparative cohort study included 55 patients with hemodynamically significant LCIV stenosis out of 285 females with PVI screened in 2014-2022. All 55 patients underwent duplex ultrasound, multi-detector computed venography, ovarian venography, and multiplanar pelvic venography.

mTert induction in p21-positive cells counteracts capillary rarefaction and pulmonary emphysema.

Lung diseases develop when telomeres shorten beyond a critical point. We constructed a mouse model in which the catalytic subunit of telomerase (mTert), or its catalytically inactive form (mTert), is expressed from the p21 locus. Expression of either TERT or TERT reduces global p21 levels in the lungs of aged mice, highlighting TERT non-canonical function.

TOP3A amplification and ATRX inactivation are mutually exclusive events in pediatric osteosarcomas using ALT.

In some types of cancer, telomere length is maintained by the alternative lengthening of telomeres (ALT) mechanism. In many ALT cancers, the α-thalassemia/mental retardation syndrome X-linked (ATRX) gene is mutated leading to the conclusion that the ATRX complex represses ALT. Here, we report that most high-grade pediatric osteosarcomas maintain their telomeres by ALT, and that the majority of these ALT tumors are ATRX wild-type (wt) and instead carry an amplified 17p11.

Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue.

Human telomere biology disorders (TBD)/short telomere syndromes (STS) are heterogeneous disorders caused by inherited loss-of-function mutations in telomere-associated genes. Here, we identify 3 germline heterozygous missense variants in the RPA1 gene in 4 unrelated probands presenting with short telomeres and varying clinical features of TBD/STS, including bone marrow failure, myelodysplastic syndrome, T- and B-cell lymphopenia, pulmonary fibrosis, or skin manifestations. All variants cluster to DNA-binding domain A of RPA1 protein.

UFMylation of MRE11 is essential for telomere length maintenance and hematopoietic stem cell survival.

Ubiquitin-fold modifier 1 (UFM1) is involved in neural and erythroid development, yet its biological roles in these processes are unknown. Here, we generated zebrafish models deficient in and that exhibited telomere shortening associated with developmental delay, impaired hematopoiesis and premature aging. We further report that HeLa cells lacking UFL1 have instability of telomeres replicated by leading-strand synthesis.

RAP1 moonlights to activate NF-κB and Notch in ALT.

Cancer cells activate either telomerase or telomere recombination (ALT) to maintain telomere length and achieve immortalization. In this issue of , Robinson reveal an unanticipated role of the protein SLX4IP in the SUMOylation of RAP1, which enhances its extratelomeric function in activating an NF-κB-Notch signaling axis that favors ALT.

Rad52 SUMOylation functions as a molecular switch that determines a balance between the Rad51- and Rad59-dependent survivors.

Functional telomeres in yeast lacking telomerase can be restored by rare Rad51- or Rad59-dependent recombination events that lead to type I and type II survivors, respectively. We previously proposed that polySUMOylation of proteins and the SUMO-targeted ubiquitin ligase Slx5-Slx8 are key factors in type II recombination. Here, we show that SUMOylation of Rad52 favors the formation of type I survivors.

Analysis of Recombination at Yeast Telomeres.

Upon telomerase inactivation telomeres are getting shorter at each round of DNA replication and progressively lose capping functions and hence protection against homologous recombination. In addition, telomerase-minus cells undergo a round of stochastic DNA damage before the bulk of telomeres become critically short because telomeres are difficult regions to replicate. Although most of the cells will enter finally replicative senescence, those that unleash recombination can eventually recover functional telomeres and growth capacity.

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.

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.

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.

[Ultrasonic geometry of synthetic endoprostheses after transabdominal preperitoneal hernioplasty of inguinal hernias].

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.

Ultrasound Appearance of Mesh After Transabdominal Preperitoneal Inguinal Hernia Repair.

The linear geometry of the meshes undergoes significant changes after the transabdominal preperitoneal (TAPP) inguinal hernia repair, caused not only by the presence or absence of mesh fixation but also by reparative processes occurring in the area of surgical intervention. To assess the position of mesh in the preperitoneal space after the TAPP inguinal hernia repair using ultrasonography in the immediate and late postoperative periods. A total of 65 patients who underwent inguinal hernia repair with TAPP were examined.

The nuclear pore complex prevents sister chromatid recombination during replicative senescence.

The Nuclear Pore Complex (NPC) has emerged as an important hub for processing various types of DNA damage. Here, we uncover that fusing a DNA binding domain to the NPC basket protein Nup1 reduces telomere relocalization to nuclear pores early after telomerase inactivation. This Nup1 modification also impairs the relocalization to the NPC of expanded CAG/CTG triplet repeats.

Structural Insights into Yeast Telomerase Recruitment to Telomeres.

Telomerase maintains chromosome ends from humans to yeasts. Recruitment of yeast telomerase to telomeres occurs through its Ku and Est1 subunits via independent interactions with telomerase RNA (TLC1) and telomeric proteins Sir4 and Cdc13, respectively. However, the structures of the molecules comprising these telomerase-recruiting pathways remain unknown.

De novo telomere addition at chromosome breaks: Dangerous Liaisons.

Telomerase counteracts the loss of terminal DNA sequences from chromosome ends; however, it may erroneously add telomeric repeats to DNA double-strand breaks. In this issue, Ouenzar et al. (2017.

Replication stress as a source of telomere recombination during replicative senescence in Saccharomyces cerevisiae.

Replicative senescence is triggered by short unprotected telomeres that arise in the absence of telomerase. In addition, telomeres are known as difficult regions to replicate due to their repetitive G-rich sequence prone to secondary structures and tightly bound non-histone proteins. Here we review accumulating evidence that telomerase inactivation in yeast immediately unmasks the problems associated with replication stress at telomeres.

SUMO-Dependent Relocalization of Eroded Telomeres to Nuclear Pore Complexes Controls Telomere Recombination.

In budding yeast, inactivation of telomerase and ensuing telomere erosion cause relocalization of telomeres to nuclear pore complexes (NPCs). However, neither the mechanism of such relocalization nor its significance are understood. We report that proteins bound to eroded telomeres are recognized by the SUMO (small ubiquitin-like modifier)-targeted ubiquitin ligase (STUbL) Slx5-Slx8 and become increasingly SUMOylated.

Rad59-facilitated acquisition of Y' elements by short telomeres delays the onset of senescence.

Telomerase-negative yeasts survive via one of the two Rad52-dependent recombination pathways, which have distinct genetic requirements. Although the telomere pattern of type I and type II survivors is well characterized, the mechanistic details of short telomere rearrangement into highly evolved pattern observed in survivors are still missing. Here, we analyze immediate events taking place at the abruptly shortened VII-L and native telomeres.

Sgs1 and Sae2 promote telomere replication by limiting accumulation of ssDNA.

In budding yeast, DNA ends are processed by the consecutive action of MRX/Sae2 and two redundant pathways dependent on Sgs1/Dna2 and Exo1, and this processing is counteracted by Ku heterodimer. Here we show that DNA end resection by Sae2 and Sgs1 is dispensable for normal telomere maintenance by telomerase. Instead, these proteins facilitate telomere replication and limit the accumulation of single-strand DNA (ssDNA) at replication fork pause sites.

Cdc13 at a crossroads of telomerase action.

Telomere elongation by telomerase involves sequential steps that must be highly coordinated to ensure the maintenance of telomeres at a proper length. Telomerase is delivered to telomere ends, where it engages single-strand DNA end as a primer, elongates it, and dissociates from the telomeres via mechanism that is likely coupled to the synthesis of the complementary C-strand. In Saccharomyces cerevisiae, the telomeric G-overhang bound Cdc13 acts as a platform for the recruitment of several factors that orchestrate timely transitions between these steps.

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).

Conserved telomere maintenance component 1 interacts with STN1 and maintains chromosome ends in higher eukaryotes.

Orthologs of the yeast telomere protein Stn1 are present in plants, but other components of the Cdc13/Stn1/Ten1 (CST) complex have only been found in fungi. Here we report the identification of conserved telomere maintenance component 1 (CTC1) in plants and vertebrates. CTC1 encodes an approximately 140 kDa telomere-associated protein predicted to contain multiple OB-fold domains.