Switch-like phosphorylation of WRN integrates end-resection with RAD51 metabolism at collapsed replication forks.

Replication-dependent DNA double-strand breaks are harmful lesions preferentially repaired by homologous recombination (HR), a process that requires processing of DNA ends to allow RAD51-mediated strand invasion. End resection and subsequent repair are two intertwined processes, but the mechanism underlying their execution is still poorly appreciated. The WRN helicase is one of the crucial factors for end resection and is instrumental in selecting the proper repair pathway.

Functional correlation between WRN and SAMHD1 in DNA end-resection.

Double-strand breaks (DSBs) can cause chromosome rearrangements, leading to cancer and some genetic diseases. WRN and SAMHD1 are proteins implicated in DSB processing and form a complex. Our study shows that SAMHD1 influences the nuclear recruitment of WRN in response to CPT-induced DSBs.

WRNIP1 prevents transcription-associated genomic instability.

R-loops are non-canonical DNA structures that form during transcription and play diverse roles in various physiological processes. Disruption of R-loop homeostasis can lead to genomic instability and replication impairment, contributing to several human diseases, including cancer. Although the molecular mechanisms that protect cells against such events are not fully understood, recent research has identified fork protection factors and DNA damage response proteins as regulators of R-loop dynamics.

Common inflammatory markers in the screening of knee arthroprosthesis infections.

Aim To evaluate the sensitivity and specificity of serum C-reactive protein (CRP) in early and late total knee arthroplasty (TKA) infections. Methods Blood tests to determine CRP levels (cut-off 10 mg/L)were conducted before surgery, at 1st day, 7th day and 15th day after surgery and at 1, 3, 6,12, 24 and 36 months. Patients had routine follow-up visits and radiological evaluations at 14 days and at 1, 3, 6, 12, 24 and 36 months.

A double-ring of human RAD52 remodels replication forks restricting fork reversal.

Unlabelled: Human RAD52 is a multifunctional DNA repair protein involved in several cellular events that support genome stability including protection of stalled DNA replication forks from excessive degradation . In its gatekeeper role, RAD52 binds to and stabilizes stalled replication forks during replication stress protecting them from reversal by SMARCAL1 . The structural and molecular mechanism of the RAD52-mediated fork protection remains elusive.

PHOSPHORYLATION-DEPENDENT ASSOCIATION OF WRN WITH RPA IS REQUIRED FOR RECOVERY OF REPLICATION FORKS STALLED AT SECONDARY DNA STRUCTURES.

The WRN protein mutated in the hereditary premature aging disorder Werner syndrome plays a vital role in handling, processing, and restoring perturbed replication forks. One of its most abundant partners, Replication Protein A (RPA), has been shown to robustly enhance WRN helicase activity in specific cases when tested . However, the significance of RPA-binding to WRN at replication forks in vivo has remained largely unexplored.

Phosphorylation status of MUS81 is a modifier of Olaparib sensitivity in BRCA2-deficient cells.

The MUS81 complex is crucial for preserving genome stability through resolution of branched DNA intermediates in mitosis and also for the processing of deprotected replication forks in BRCA2-deficient cells. Because of the existence of two different MUS81 complexes in mammalian cells that act in M- or S-phase, whether and how the PARPi sensitivity of BRCA2-deficient cells is affected by loss of MUS81 function is unclear. Here, using a mutant of MUS81 that impairs its function in M-phase, we show that viability of BRCA2-deficient cells but not their PARPi sensitivity requires a fully-functional MUS81 complex in mitosis.

Therapeutic disruption of RAD52-ssDNA complexation via novel drug-like inhibitors.

RAD52 protein is a coveted target for anticancer drug discovery. Similar to poly-ADP-ribose polymerase (PARP) inhibitors, pharmacological inhibition of RAD52 is synthetically lethal with defects in genome caretakers BRCA1 and BRCA2 (∼25% of breast and ovarian cancers). Emerging structure activity relationships for RAD52 are complex, making it challenging to transform previously identified disruptors of the RAD52-ssDNA interaction into drug-like leads using traditional medicinal chemistry approaches.

RAD52 prevents accumulation of -dependent replication gaps at perturbed replication forks in human cells.

Replication gaps can arise as a consequence of perturbed DNA replication and their accumulation might undermine the stability of the genome. Loss of RAD52, a protein involved in the regulation of fork reversal, promotes accumulation of parental ssDNA gaps during replication perturbation. Here, we demonstrate that this is due to the engagement of downstream of the extensive degradation of perturbed replication forks after their reversal, and is not dependent on PrimPol.

SHP2's gain-of-function in Werner syndrome causes childhood disease onset likely resulting from negative genetic interaction.

Prompt diagnosis of complex phenotypes is a challenging task in clinical genetics. Whole exome sequencing has proved to be effective in solving such conditions. Here, we report on an unpredictable presentation of Werner Syndrome (WRNS) in a 12-year-old girl carrying a homozygous truncating variant in RECQL2, the gene mutated in WRNS, and a de novo activating missense change in PTPN11, the major Noonan syndrome gene, encoding SHP2, a protein tyrosine phosphatase positively controlling RAS function and MAPK signaling, which have tightly been associated with senescence in primary cells.

R-Loop-Associated Genomic Instability and Implication of WRN and WRNIP1.

Maintenance of genome stability is crucial for cell survival and relies on accurate DNA replication. However, replication fork progression is under constant attack from different exogenous and endogenous factors that can give rise to replication stress, a source of genomic instability and a notable hallmark of pre-cancerous and cancerous cells. Notably, one of the major natural threats for DNA replication is transcription.

Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51.

Cancer stem cells (CSCs) are tumor subpopulations driving disease development, progression, relapse and therapy resistance, and their targeting ensures tumor eradication. CSCs display heterogeneous replication stress (RS), but the functionality/relevance of the RS response (RSR) centered on the ATR-CHK1 axis is debated. Here, we show that the RSR is efficient in primary CSCs from colorectal cancer (CRC-SCs), and describe unique roles for PARP1 and MRE11/RAD51.

Platet Rich Plasma or Hyperbaric Oxygen Therapy as callus accellerator in aseptic tibial non union. Evaluate of outcomes.

Background And Aim Of The Work: The incidence of long bone non-unions has been estimated to range between 5-10%. Nonunion of fracture is a delayed complication of fracture. A large bone resection, associated with Ilizarov's osteo-distraction technique, is commonly used in these cases.

Reliability of S.A.R.A. (sterilization and reimplantation autograft) technique in long bone open fractures.

The reimplantation of small or large extruded bone segments is one of the most complex clinical management scenarios in the treatment of open fractures. No consensus exists regarding the efficiency of this technique. The aim of the study was to analyse the clinical and radiological outcomes of Sterilization and Reimplantation Autograft (S.

Bone grafiting combined with Sauvé-Kapandji Procedures for the treatment of aseptic distal radius non-union.

Distal radius fractures are the most common type of upper limb fractures in adults. Non-union after distal radius fracture is rare, serious and unpredictable. The aim of our paper is to analyse the clinical and radiological outcomes of bone grafting and Sauvé-Kapandji Procedures for the treatment of aseptic distal radius non-union.

Using a Human Papillomavirus Model to Study DNA Replication and Repair of Wild Type and Damaged DNA Templates in Mammalian Cells.

Human papillomaviruses have 8kbp DNA episomal genomes that replicate autonomously from host DNA. During initial infection, the virus increases its copy number to 20-50 copies per cell, causing torsional stress on the replicating DNA. This activates the DNA damage response (DDR) and HPV replicates its genome, at least in part, using homologous recombination.

Surgical treatment of multifragmentary segmental femur shaft fractures with ORIF and bone graft versus MIPO: a prospective control-group study.

Aim Multifragmentary segmental femoral shaft fracture is a high energy injury frequently associated with life-threatening conditions. The aim of this study was to compare the use of bio metallic open reduction internal fixation (ORIF) (plate with allograft bone strut) with minimally invasive plate osteosynthesis (MIPO) fixation for the treatment of multi-segmental femoral shaft fracture in terms of outcomes, bone healing and complications. Methods Forty patients with segmental femoral shaft fractures were included and divided into two groups: 20 patients treated with ORIF+, 20 with MIPO.

Reverse transcriptase inhibitors promote the remodelling of nuclear architecture and induce autophagy in prostate cancer cells.

Emerging data indicate that the reverse transcriptase (RT) protein encoded by LINE-1 transposable elements is a promising cancer target. Nonnucleoside RT inhibitors, e.g.

Physiological and Pathological Roles of RAD52 at DNA Replication Forks.

Understanding basic molecular mechanisms underlying the biology of cancer cells is of outmost importance for identification of novel therapeutic targets and biomarkers for patient stratification and better therapy selection. One of these mechanisms, the response to replication stress, fuels cancer genomic instability. It is also an Achille's heel of cancer.

Checkpoint Defects Elicit a WRNIP1-Mediated Response to Counteract R-Loop-Associated Genomic Instability.

Conflicts between replication and transcription are a common source of genomic instability, a characteristic of almost all human cancers. Aberrant R-loops can cause a block to replication fork progression. A growing number of factors are involved in the resolution of these harmful structures and many perhaps are still unknown.

Grafting and fixation after aseptic non-union of the humeral shaft: A case series.

Purpose: Non-unions after humeral shaft fractures are seen frequently in clinical practice at about 2-10% after conservative management and 30% after surgical treatment. Non-union, displacement of structures and fixation failure can be hazardous complications. The purpose of our study was to evaluate the outcomes of an on-lay bone graft strut construction with bone chips as grafting augmentation in the management of aseptic non-unions of the humeral shaft.

Plate-and-bone-strut fixation of distal third humeral shaft aseptic non-unions: A consecutive case series.

Introduction: Non-union after humeral shaft fractures are seen frequently in clinical practice. The incidence is 2-10% after conservative management and up to 30% after surgical treatment. The purpose of this study is to evaluate the outcomes of plate-and-bone-strut-allograft technique with bone chip augmentation for aseptic non-unions of the distal third of the humerus.

Standard plating vs. cortical strut and plating for periprosthetic knee fractures: a multicentre experience.

Aim Periprosthetic fracture after knee arthroplasty occurs more frequently in the supracondylar area of femur, especially after low energy trauma associated with torsional or compressive forces. Several techniques have been described for the treatment of displaced fractures. The aim of this study is the evaluation of the outcomes and bone healing of periprosthetic femoral fractures managed by standard plate fixation compared to plating with bone grafting.

Efficacy of the "Salento technique", a modified two-incision approach in distal biceps brachii tendon repair. Surgical description and outcomes analysis.

Introduction: The biceps brachii lesion needs to be treated surgically. A modified two incisions technique is proposed and reviewed. Material and Methods: All patients were treated with the same technique.

Inducible SMARCAL1 knockdown in iPSC reveals a link between replication stress and altered expression of master differentiation genes.

Schimke immuno-osseous dysplasia is an autosomal recessive genetic osteochondrodysplasia characterized by dysmorphism, spondyloepiphyseal dysplasia, nephrotic syndrome and frequently T cell immunodeficiency. Several hypotheses have been proposed to explain the pathophysiology of the disease; however, the mechanism by which mutations cause the syndrome is elusive. Here, we generated a conditional SMARCAL1 knockdown model in induced pluripotent stem cells (iPSCs) to mimic conditions associated with the severe form the disease.