Patients with chronic kidney disease (CKD) are at an increased risk of premature mortality, mainly from cardiovascular causes. The association between CKD on hemodialysis and accelerated atherosclerosis was described >40 years ago. However, more recently, it has been suggested that the increase in atherosclerosis risk is actually observed in early CKD stages, remaining stable thereafter. In this regard, interventions targeting the pathogenesis of atherosclerosis, such as statins, successful in the general population, have failed to benefit patients with very advanced CKD. This raises the issue of the relative contribution of atherosclerosis versus other forms of cardiovascular injury such as arteriosclerosis or myocardial injury to the increased cardiovascular risk in CKD. In this review, the pathophysiogical contributors to atherosclerosis in CKD that are shared with the general population, or specific to CKD, are discussed. The NEFRONA study (Observatorio Nacional de Atherosclerosis en NEFrologia) prospectively assessed the prevalence and progression of subclinical atherosclerosis (plaque in vascular ultrasound), confirming an increased prevalence of atherosclerosis in patients with moderate CKD. However, the adjusted odds ratio for subclinical atherosclerosis increased with CKD stage, suggesting a contribution of CKD itself to subclinical atherosclerosis. Progression of atherosclerosis was closely related to CKD progression as well as to the baseline presence of atheroma plaque, and to higher phosphate, uric acid, and ferritin and lower 25(OH) vitamin D levels. These insights may help design future clinical trials of stratified personalized medicine targeting atherosclerosis in patients with CKD. Future primary prevention trials should enroll patients with evidence of subclinical atherosclerosis and should provide a comprehensive control of all known risk factors in addition to testing any additional intervention or placebo.

The RecQ helicase Sgs1 plays critical roles during DNA repair by homologous recombination, from end resection to Holliday junction (HJ) dissolution. Sgs1 has both pro- and anti-recombinogenic roles, and therefore its activity must be tightly regulated. However, the controls involved in recruitment and activation of Sgs1 at damaged sites are unknown. Here we show a two-step role for Smc5/6 in recruiting and activating Sgs1 through SUMOylation. First, auto-SUMOylation of Smc5/6 subunits leads to recruitment of Sgs1 as part of the STR (Sgs1–Top3–Rmi1) complex, mediated by two SUMO-interacting motifs (SIMs) on Sgs1 that specifically recognize SUMOylated Smc5/6. Second, Smc5/6-dependent SUMOylation of Sgs1 and Top3 is required for the efficient function of STR. Sgs1 mutants impaired in recognition of SUMOylated Smc5/6 (sgs1-SIMΔ) or SUMO-dead alleles (sgs1-KR) exhibit unprocessed HJs at damaged replication forks, increased crossover frequencies during double-strand break repair, and severe impairment in DNA end resection. Smc5/6 is a key regulator of Sgs1's recombination functions.

Mitotic chromosome segregation requires the removal of physical connections between sister chromatids. In addition to cohesin and topological entrapments, sister chromatid separation can be prevented by the presence of chromosome junctions or ongoing DNA replication. We will collectively refer to them as DNA-mediated linkages. Although this type of structures has been documented in different DNA replication and repair mutants, there is no known essential mechanism ensuring their timely removal before mitosis. Here, we show that the dissolution of these connections is an active process that requires the Smc5/6 complex, together with Mms21, its associated SUMO-ligase. Failure to remove DNA-mediated linkages causes gross chromosome missegregation in anaphase. Moreover, we show that Smc5/6 is capable to dissolve them in metaphase-arrested cells, thus restoring chromosome resolution and segregation. We propose that Smc5/6 has an essential role in the removal of DNA-mediated linkages to prevent chromosome missegregation and aneuploidy.

Background: Chronic kidney disease (CKD) is an independent risk factor for atherosclerotic disease. We hypothesized that CKD promotes a proatherogenic lipid profile modifying lipoprotein composition and particle number. Methods: Cross-sectional study in 395 non-diabetic individuals (209 CKD patients and 186 controls) without statin therapy. Conventional lipid determinations were combined with advanced lipoprotein profiling by nuclear magnetic resonance, and their discrimination ability was assessed by machine learning. Results: CKD patients showed an increase of very-low-density (VLDL) particles and a reduction of LDL particle size. Cholesterol and triglyceride content of VLDLs and intermediate-density (IDL) particles increased. However, low-density (LDL) and high-density (HDL) lipoproteins gained triglycerides and lost cholesterol. Total-Cholesterol, HDL-Cholesterol, LDL-Cholesterol, non-HDL-Cholesterol and Proprotein convertase subtilsin-kexin type (PCSK9) were negatively associated with CKD stages, whereas triglycerides, lipoprotein(a), remnant cholesterol, and the PCSK9/LDL-Cholesterol ratio were positively associated. PCSK9 was positively associated with total-Cholesterol, LDL-Cholesterol, LDL-triglycerides, LDL particle number, IDL-Cholesterol and remnant cholesterol. Machine learning analysis by random forest revealed that new parameters have a higher discrimination ability to classify patients into the CKD group, compared to traditional parameters alone: area under the curve (95% CI), .789 (.711, .853) vs .687 (.611, .755), respectively. Conclusions: non-diabetic CKD patients have a hidden proatherogenic lipoprotein profile.

Modification of proteins by SUMO is essential for the maintenance of genome integrity. During DNA replication, the Mms21-branch of the SUMO pathway counteracts recombination intermediates at damaged replication forks, thus facilitating sister chromatid disjunction. The Mms21 SUMO ligase docks to the arm region of the Smc5 protein in the Smc5/6 complex; together, they cooperate during recombinational DNA repair. Yet how the activity of the SUMO ligase is controlled remains unknown. Here we show that the SUMO ligase and the chromosome disjunction functions of Mms21 depend on its docking to an intact and active Smc5/6 complex, indicating that the Smc5/6-Mms21 complex operates as a large SUMO ligase in vivo. In spite of the physical distance separating the E3 and the nucleotide-binding domains in Smc5/6, Mms21-dependent sumoylation requires binding of ATP to Smc5, a step that is part of the ligase mechanism that assists Ubc9 function. The communication is enabled by the presence of a conserved disruption in the coiled coil domain of Smc5, pointing to potential conformational changes for SUMO ligase activation. In accordance, scanning force microscopy of the Smc5-Mms21 heterodimer shows that the molecule is physically remodeled in an ATP-dependent manner. Our results demonstrate that the ATP-binding activity of the Smc5/6 complex is coordinated with its SUMO ligase, through the coiled coil domain of Smc5 and the physical remodeling of the molecule, to promote sumoylation and chromosome disjunction during DNA repair. The modification of target proteins by conjugation to SUMO—a small protein that acts as a regulatory tag—is essential for maintaining the integrity of genomes in most eukaryotic organisms. One critical step during the attachment of SUMO is the activation of the enzymes that catalyze this reaction—E1, E2, and the SUMO ligases. However, we currently do not fully understand how the different enzymes in the SUMO pathway are regulated. The SUMO ligase Mms21 is known to bind to Smc5/6, a large protein complex involved in the structural maintenance of chromosomes. Both Mms21 and Smc5/6 counteract the accumulation of recombination intermediates, which otherwise join replicated chromosomes, preventing their separation. Not surprisingly, the few known targets of the Mms21 ligase are mostly related to the repair of sister chromatids by recombination. Here, we show that the Mms21 SUMO ligase needs to bind to the Smc5/6 complex to promote chromosome separation. We used two Mms21-dependent SUMO conjugation targets—Smc5 and cohesin—to study the connection between the Mms21’s SUMO ligase activity and its binding partner, Smc5/6. Our results indicated that Mms21 activation is tightly coordinated with the intrinsic ATPase function of the Smc5/6 complex. However, the SUMO ligase and the ATPase lie in different domains of the Smc5/6-Mms21 complex that are normally distant from each other; we show that communication between these enzyme sites is enabled by the presence of conserved joints, which we suggest allow the necessary conformational changes required for SUMO ligase activation. This coordination of activities is extremely helpful for the cell, enabling it to integrate a structural role on chromatin during DNA repair with a signaling function, thereby promoting correct separation of the chromosomes.