Search

The DNA repair capacity of human cells declines with age, in a process that is not clearly understood. Mutation of the nuclear envelope protein barrier-to-autointegration factor 1 (Banf1) has previously been shown to cause a human progeroid disorder, Néstor–Guillermo progeria syndrome (NGPS). The underlying links between Banf1, DNA repair and the ageing process are unknown. Here, we report that Banf1 controls the DNA damage response to oxidative stress via regulation of poly [ADP-ribose] polymerase 1 (PARP1). Specifically, oxidative lesions promote direct binding of Banf1 to PARP1, a critical NAD+-dependent DNA repair protein, leading to inhibition of PARP1 auto-ADP-ribosylation and defective repair of oxidative lesions, in cells with increased Banf1. Consistent with this, cells from patients with NGPS have defective PARP1 activity and impaired repair of oxidative lesions. These data support a model whereby Banf1 is crucial to reset oxidative-stress-induced PARP1 activity. Together, these data offer insight into Banf1-regulated, PARP1-directed repair of oxidative lesions., Mutation of the nuclear envelope protein, barrier-to-autointegration factor 1 (Banf1), has previously been associated with the development of ageing associated diseases in a human progeria syndrome. Here, the authors reveal the functional link between Banf1-regulated, PARP1-directed repair of oxidative lesions.

Genomic stability is critical for normal cellular function and its deregulation is a universal hallmark of cancer. Here we outline a previously undescribed role of COMMD4 in maintaining genomic stability, by regulation of chromatin remodelling at sites of DNA double-strand breaks. At break-sites, COMMD4 binds to and protects histone H2B from monoubiquitination by RNF20/RNF40. DNA damage-induced phosphorylation of the H2A-H2B heterodimer disrupts the dimer allowing COMMD4 to preferentially bind H2A. Displacement of COMMD4 from H2B allows RNF20/40 to monoubiquitinate H2B and for remodelling of the break-site. Consistent with this critical function, COMMD4-deficient cells show excessive elongation of remodelled chromatin and failure of both non-homologous-end-joining and homologous recombination. We present peptide-mapping and mutagenesis data for the potential molecular mechanisms governing COMMD4-mediated chromatin regulation at DNA double-strand breaks., Amila Suraweera et al. use a range of biochemical and in vitro cellular assays to examine the role of the COMMD4 in DNA repair. Their results suggest that COMMD4 interacts with the histone H2A-H2B during repair of double-stranded DNA breaks, thereby maintaining genomic stability by regulating chromatin structure.

Background:Reactive Oxygen Species (ROS) are by-products of normal cellular metabolic processes, such as mitochondrial oxidative phosphorylation. While low levels of ROS are important signalling molecules, high levels of ROS can damage proteins, lipids and DNA. Indeed, oxidative DNA damage is the most frequent type of damage in the mammalian genome and is linked to human pathologies such as cancer and neurodegenerative disorders. Although oxidative DNA damage is cleared predominantly through the Base Excision Repair (BER) pathway, recent evidence suggests that additional pathways such as Nucleotide Excision Repair (NER) and Mismatch Repair (MMR) can also participate in clearance of these lesions. One of the most common forms of oxidative DNA damage is the base damage 8-oxoguanine (8-oxoG), which if left unrepaired may result in G:C to A:T transversions during replication, a common mutagenic feature that can lead to cellular transformation.Objective:Repair of oxidative DNA damage, including 8-oxoG base damage, involves the functional interplay between a number of proteins in a series of enzymatic reactions. This review describes the role and the redox regulation of key proteins involved in the initial stages of BER of 8-oxoG damage, namely Apurinic/Apyrimidinic Endonuclease 1 (APE1), human 8-oxoguanine DNA glycosylase-1 (hOGG1) and human single-stranded DNA binding protein 1 (hSSB1). Moreover, the therapeutic potential and modalities of targeting these key proteins in cancer are discussed.Conclusion:It is becoming increasingly apparent that some DNA repair proteins function in multiple repair pathways. Inhibiting these factors would provide attractive strategies for the development of more effective cancer therapies.

ATM is the most significant molecule involved in monitoring the genomic integrity of the cell. Any damage done to DNA relentlessly challenges the cellular machinery involved in recognition, processing and repair of these insults. ATM kinase is activated early to detect and signal lesions in DNA, arrest the cell cycle, establish DNA repair signaling and faithfully restore the damaged chromatin. ATM activation plays an important role as a barrier to tumorigenesis, metabolic syndrome and neurodegeneration. Therefore, studies of ATM-dependent DNA damage signaling pathways hold promise for treatment of a variety of debilitating diseases through the development of new therapeutics capable of modulating cellular responses to stress. In this review, we have tried to untangle the complex web of ATM signaling pathways with the purpose of pinpointing multiple roles of ATM underlying the complex phenotypes observed in AT patients.

Aim Minimally invasive approaches for stoma closure offer considerable benefits for patients. Single port access via an end ileostomy site after stoma take-down in patients with prior total colectomy and a rectal stump remnant could allow restoration of ileorectal continuity by anastomosis but has not been detailed previously. Methods After mobilisation of the end ileostomy, the anvil of a circular stapler is secured into the open end of the distal ileum and the intestine returned into the abdominal cavity. A single port access device (in this description, a ‘surgical glove port’) is placed then into the stoma site and full laparoscopy performed. Once the rectal stump is identified and prepared, an intracorporeal anastomosis can be constructed in a tension-free manner using a Knight-Griffin technique. Leak-testing can also be performed and the operation concluded with closure of the solitary incision. Results In selected cases, adhesiolysis and anastomosis can be safely performed in toto. If the peritoneal environment is challenging, access can be escalated to multiport laparoscopy or even laparotomy. Conclusion Initiation of ileorectal anastomosis construction by single port laparoscopy at least allows peritoneal assessment but can provide for the operation's completion. This can confer maximum patient benefit for the most minimally invasive option.

Research on prostate cancer progression has focused extensively on the concept of miRNA, which can operate either as promoters or as suppressors of carcinogenesis. Moreover, recent genetic studies and emerging functional work show that strikingly similar and overlapping pathways are involved in prostate carcinogenesis. Unswervingly, these elements constitute a recently explored ‘network of networks’ that dynamically reorganizes during DNA damage and is responsible for positively or negatively regulating genome organization and integrity. We consider these facets of convergence and discuss how insights from diametrically opposed interactions of ataxia–telangiectasia mutated and mitrons can inform us about, and possibly help us to get a step closer to personalized medicine. Copyright © 2012 John Wiley & Sons, Ltd.

A 64-year-old man presented with right-sided abdominal pain. CT demonstrated an inflamed Meckel’s diverticulum (MD) (figure 1). Single-incision laparoscopy (SILS) was performed (figure 2) and MD was identified and exteriorised. Extracorporeal resection and anastomosis of small bowel containing MD was performed. The patient recovered well and was discharged home 2 days later. Figure 1 CT images demonstrating inflamed Meckel's diverticulum (MD) (red arrow). Figure 2 Intraoperative image demonstrating (A) the glove port technique which uses a sterile glove for the insertion of three standard …

We present a case of a 68-year-old female who presented to the emergency department with shortness of breath and right shoulder pain after falling down a flight of stairs. Chest x-ray revealed multiple rib fractures and a large haemothorax on the right side (figure 1A). x-Ray of the humerus showed a complex fracture of the surgical neck of the humerus with …