Non-redundant roles in sister chromatid cohesion of the DNA helicase DDX11 and the SMC3 acetyl transferases ESCO1 and ESCO2.
DNA解旋酶DDX11 和SMC3 乙酰转移酶ESCO1 和esco2 的姐妹染色单体内聚力中的非冗余作用。
- 作者列表："Faramarz A","Balk JA","van Schie JJM","Oostra AB","Ghandour CA","Rooimans MA","Wolthuis RMF","de Lange J
:In a process linked to DNA replication, duplicated chromosomes are entrapped in large, circular cohesin complexes and functional sister chromatid cohesion (SCC) is established by acetylation of the SMC3 cohesin subunit. Roberts Syndrome (RBS) and Warsaw Breakage Syndrome (WABS) are rare human developmental syndromes that are characterized by defective SCC. RBS is caused by mutations in the SMC3 acetyltransferase ESCO2, whereas mutations in the DNA helicase DDX11 lead to WABS. We found that WABS-derived cells predominantly rely on ESCO2, not ESCO1, for residual SCC, growth and survival. Reciprocally, RBS-derived cells depend on DDX11 to maintain low levels of SCC. Synthetic lethality between DDX11 and ESCO2 correlated with a prolonged delay in mitosis, and was rescued by knockdown of the cohesin remover WAPL. Rescue experiments using human or mouse cDNAs revealed that DDX11, ESCO1 and ESCO2 act on different but related aspects of SCC establishment. Furthermore, a DNA binding DDX11 mutant failed to correct SCC in WABS cells and DDX11 deficiency reduced replication fork speed. We propose that DDX11, ESCO1 and ESCO2 control different fractions of cohesin that are spatially and mechanistically separated.
: 在与DNA复制相关的过程中，重复的染色体被包埋在大的、环状的黏连蛋白复合物中，功能姐妹染色单体内聚力 (SCC) 是通过SMC3 黏连蛋白亚基的乙酰化建立的。罗伯茨综合征 (RBS) 和华沙断裂综合征 (WABS) 是罕见的以SCC缺陷为特征的人类发育综合征。RBS是由SMC3 乙酰转移酶ESCO2 的突变引起的，而DNA解旋酶DDX11 的突变导致WABS。我们发现WABS来源的细胞主要依赖ESCO2，而不是ESCO1 来维持残余SCC、生长和存活。反之，RBS来源的细胞依赖DDX11 维持低水平的SCC。DDX11 和ESCO2 之间的合成致死率与有丝分裂的延长延迟相关，并通过敲除黏连蛋白去除剂WAPL而获救。使用人或小鼠cdna的拯救实验揭示了DDX11 、ESCO1 和ESCO2 作用于SCC建立的不同但相关的方面。此外，DNA结合DDX11 突变体未能纠正WABS细胞中的SCC，DDX11 缺陷降低了复制叉速度。我们提出DDX11 、ESCO1 和ESCO2 控制空间和机械分离的不同部分的黏连蛋白。
METHODS::Impairments in social cognition have been frequently described in 22q11.2 deletion syndrome (22q11.2DS) and are thought to be a hallmark of difficulties in social interactions. The present study addresses aspects that are critical for everyday social cognitive functioning but have received little attention so far. Sixteen children with 22q11.2DS and 22 controls completed 1 task of facial expression recognition, 1 task of attribution of facial expressions to faceless characters involved in visually presented social interactions, and 1 task of attribution of facial expressions to characters involved in aurally presented dialogues. All three tasks have in common to involve processing of emotions. All participants also completed two tasks of attention and two tasks of visual spatial perception, and their parents completed some scales regarding behavioural problems of their children. Patients performed worse than controls in all three tasks of emotion processing, and even worse in the second and third tasks. However, they performed above chance level in all three tasks, and the results were independent of IQ, age and gender. The analysis of error patterns suggests that patients tend to coarsely categorize situations as either attractive or repulsive and also that they have difficulties in differentiating emotions that are associated with threats. An isolated association between the tasks of emotion and behaviour was found, showing that the more frequently patients with 22q11.2DS perceive happiness where there is not, the less they exhibit aggressive behaviour.
METHODS:BACKGROUND:We describe the first radiographic clinic in the literature for DDH and how this novel clinic can significantly improve the efficiency and cost-effectiveness of service in a tertiary referral centre. AIMS:A radiographic clinic for the management of developmental dysplasia of the hip was introduced in 2017 in our institution. We performed a detailed cost analysis to assess the economic savings made with the introduction of this new clinic. We assessed the efficiency of the service by identifying how many unnecessary outpatient visits were prevented. We also assessed the difference in times from referral to review between the two clinics. METHODS:Analysis of the clinic activity in 2017 was possible as all data was collected prospectively by the DDH CNS and stored in our database. Cost analysis was performed, and the savings made per patient along with the financial benefit to our institution was recorded. RESULTS:The new radiographic clinic reduced the cost of reviewing one patient by €162.51 per patient. There was a 73% discharge rate from the clinic which prevented 251 unnecessary patient visits to the outpatient department over the course of the year. There was a significant 11-day reduction in waiting times between referral and review when comparing the radiographic to the conventional clinic (p < 0.05). CONCLUSIONS:A radiographic clinic for the management of developmental dysplasia of the hip has a significant effect on the efficiency and overall cost-effectiveness of service provision in a tertiary referral centre.
METHODS:INTRODUCTION:Triple pelvic osteotomy (TPO) involves periacetabular osteotomies of the ilium, ischium, and pubis to reorient the acetabulum. This operation is indicated in certain situations for the treatment of developmental dysplasia of the hip, dysplastic neuromuscular hips, and for containment of the femoral head in cases of Legg-Calvé-Perthes disease. METHODS:This retrospective cohort study compares radiographic outcomes of patients who underwent TPO using two different techniques and describes a novel single-incision direct lateral approach. TPO was performed on 22 patients by the senior author. The first 10 patients underwent TPO through a single-incision anterolateral approach. The last 12 patients underwent TPO using the direct lateral approach. Preoperative and postoperative pelvic radiographs were reviewed for each patient, and the migration index and center-edge angle were recorded. RESULTS:The migration index and center-edge angle were evaluated and were not found to be significantly different between the anterolateral and direct lateral groups. The direct lateral approach is described. CONCLUSION:The direct lateral approach for TPO is equivalent to the anterolateral approach on radiographic evaluation. Advantages of the direct lateral approach include direct visualization of the ischial osteotomy, effective mobilization of the acetabulum, and safety of the sciatic nerve.