Cooperativity between Cas9 and hyperactive AID establishes broad and diversifying mutational footprints in base editors.

The partnership of DNA deaminase enzymes with CRISPR-Cas nucleases is now a well-established method to enable targeted genomic base editing. However, an understanding of how Cas9 and DNA deaminases collaborate to shape base editor (BE) outcomes has been lacking. Here, we support a novel mechanistic model of base editing by deriving a range of hyperactive activation-induced deaminase (AID) base editors (hBEs) and exploiting their characteristic diversifying activity. Our model involves multiple layers of previously underappreciated cooperativity in BE steps including: (i) Cas9 binding can potentially expose both DNA strands for 'capture' by the deaminase, a feature that is enhanced by guide RNA mismatches; (ii) after strand capture, the intrinsic activity of the DNA deaminase can tune window size and base editing efficiency; (iii) Cas9 defines the boundaries of editing on each strand, with deamination blocked by Cas9 binding to either the PAM or the protospacer and (iv) non-canonical edits on the guide RNA bound strand can be further elicited by changing which strand is nicked by Cas9. Leveraging insights from our mechanistic model, we create novel hBEs that can remarkably generate simultaneous C > T and G > A transitions over >65 bp with significant potential for targeted gene diversification.

UMAD1 contributes to ESCRT-III dynamic subunit turnover during cytokinetic abscission.

Abscission is the final stage of cytokinesis whereby the midbody, a thin intercellular bridge, is resolved to separate the daughter cells. Cytokinetic abscission is mediated by the endosomal sorting complex required for transport (ESCRT), a conserved membrane remodelling machinery. The midbody organiser CEP55 recruits early acting ESCRT factors such as ESCRT-I and ALIX (also known as PDCD6IP), which subsequently initiate the formation of ESCRT-III polymers that sever the midbody. We now identify UMAD1 as an ESCRT-I subunit that facilitates abscission. UMAD1 selectively associates with VPS37C and VPS37B, supporting the formation of cytokinesis-specific ESCRT-I assemblies. TSG101 recruits UMAD1 to the site of midbody abscission, to stabilise the CEP55-ESCRT-I interaction. We further demonstrate that the UMAD1-ESCRT-I interaction facilitates the final step of cytokinesis. Paradoxically, UMAD1 and ALIX co-depletion has synergistic effects on abscission, whereas ESCRT-III recruitment to the midbody is not inhibited. Importantly, we find that both UMAD1 and ALIX are required for the dynamic exchange of ESCRT-III subunits at the midbody. Therefore, UMAD1 reveals a key functional connection between ESCRT-I and ESCRT-III that is required for cytokinesis.

Independent Recruitment of Different Types of Phospholipases A2 to the Venoms of Caenophidian Snakes: The Rise of PLA2-IIE within Pseudoboini (Dipsadidae).

Snake venoms harbor a wide and diverse array of enzymatic and nonenzymatic toxic components, allowing them to exert myriad effects on their prey. However, they appear to trend toward a few optimal compositional scaffolds, dominated by four major toxin classes: SVMPs, SVSPs, 3FTxs, and PLA2s. Nevertheless, the latter appears to be restricted to vipers and elapids, as it has never been reported as a major venom component in rear-fanged species. Here, by investigating the original transcriptomes from 19 species distributed in eight genera from the Pseudoboini tribe (Dipsadidae: Xenodontinae) and screening among seven additional tribes of Dipsadidae and three additional families of advanced snakes, we discovered that a novel type of venom PLA2, resembling a PLA2-IIE, has been recruited to the venom of some species of the Pseudoboini tribe, where it is a major component. Proteomic and functional analyses of these venoms further indicate that these PLA2s play a relevant role in the venoms from this tribe. Moreover, we reconstructed the phylogeny of PLA2s across different snake groups and show that different types of these toxins have been recruited in at least five independent events in caenophidian snakes. Additionally, we present the first compositional profiling of Pseudoboini venoms. Our results demonstrate how relevant phenotypic traits are convergently recruited by different means and from homologous and nonhomologous genes in phylogenetically and ecologically divergent snake groups, possibly optimizing venom composition to overcome diverse adaptative landscapes.

Negative association of steroids with immunotherapy efficacy in a multi-tumor cohort: time and dose-dependent.

Previous studies have suggested a negative impact of steroids on the efficacy of immune checkpoint inhibitors (ICI), but how this effect is modulated by the dosage and time of administration is yet to be clarified. We have performed a retrospective analysis of 475 patients with advanced solid tumors treated with ICI as monotherapy from 2015 to 2022. Data regarding immune-related adverse events (irAEs) and clinical outcomes were collected. For each patient, the daily steroid dose (in mg/kg of prednisone) was registered until disease progression or death. The impact of cumulative doses on response rates and survival outcomes was analyzed within different periods. The objective response rate (ORR) was significantly lower among patients exposed to steroids within 30 days before the first cycle of ICI (C1) (20.3% vs. 36.7%, p < 0.01) and within the first 90 days of treatment (25.7% vs. 37.7%, p = 0.01). This negative association was confirmed by multivariable analysis. Higher mean steroid doses were observed among non-responders, and cumulative doses were inversely correlated with the disease control rate (DCR) around ICI initiation. Remarkably, poorer outcomes were observed even in patients belonging to the lowest dose quartile compared to the steroid-naïve population. The exposure to steroids after 6 months of ICI was not associated with worse survival outcomes. Our results suggest that the potential impact of steroids on ICI efficacy may be time-dependent, prevailing around ICI initiation, and dose-dependent, with modulation of neutrophil-to-lymphocyte ratio as a possible underlying mechanism.

Effect of the Lacticaseibacillus paracasei JLM Strain Against Brucella abortus Strains in Ripened Cheese.

This study evaluated the antagonistic effect of the Lacticaseibacillus paracasei JLM strain isolated from aguamiel, against Brucella abortus RB51, S19, and 2308 strains, during the manufacture of soft-ripened cheese. First, the tolerance of Lc. paracasei JLM was tested with pH values and bile salt concentrations for 3 h to simulate digestive tract conditions. The antagonistic effect against B. abortus strains was evaluated through double-layer diffusion and agar well diffusion assays. In addition, the stability of the cell-free supernatant (CFS) was tested with the agar well diffusion method under different conditions of temperature, pH, and treatment with digestive enzymes. Finally, the antagonistic effect against B. abortus strains was observed during the manufacture of ripened cheese for 31 days at 4°C and 25°C using the Lc. paracasei JLM strain as starter culture. The results showed that the Lc. paracasei JLM strain remains viable after exposure to different pH values (from 3.00 to 7.00) and concentrations of bile salts (from 0.5% to 7%). Moreover, the results demonstrate that the growth of the three B. abortus strains was inhibited in both antagonism tests and that CFS maintained 86% activity after heat treatment at 100°C, 121°C, or enzymatic digestion (proteinase K, trypsin, chymotrypsin), but it was inactivated at pH levels above 6. Finally, Lc. paracasei JLM completely inhibited the growth of B. abortus in ripened cheese at 25°C from day 17 and showed greater inhibition on the B. abortus RB51 strain in the ripened cheese at 4°C, showing statistical differences for the B. abortus S19 and B. abortus 2308 strains. The current research concluded that the Lc. paracasei JLM strain has an antagonistic effect on B. abortus, enhancing the potential of its use in the future as a probiotic.

Relation between resilience and personality traits: The role of hopelessness and age.

Resilience refers to the process by which individuals use the ability to cope with challenges to successfully adapt to adverse situations, inclining towards the future and hope. The main aim of this study was to analyze the relation between resilience, personality traits, and hopelessness. Furthermore, we conducted comparisons between two age groups: young and older adults. The sample comprised 439 Spanish participants (66.7% women; M = 43.73, SD = 26.41; age range = 18-98 years). The Connor-Davidson Resilience Scale, NEO-Five Factor Inventory, and Beck Hopelessness Scale were used to measure the main study variables. The results revealed a negative relation between resilience and neuroticism, and a positive association with the other personality traits. Additionally, levels of resilience were found to be negatively related to hopelessness. The group of older adults showed significantly lower resilience levels than the young adults, although age was not a significant predictor of resilience. Neuroticism, extraversion, openness, and hopelessness were the only predictors of resilience for the current study. This work contributes to the study of resilience and related factors, by attempting to understand the role of resilience and resistance to risk and how individuals tackle challenges over time, with important implications for mental health.

Maternal mortality trends in Spain during the 2000-2018 period: the role of maternal origin.

BACKGROUND: The available literature indicates that there are significant differences in maternal mortality according to maternal origin in high income countries. The aim of this study was to examine the trend in the maternal mortality rate and its most common causes in Spain in recent years and to analyse its relationship with maternal origin. METHODS: This was a cross-sectional study of all live births as well as those resulting in maternal death in Spain during the period between 2000 and 2018. A descriptive analysis of the maternal mortality rate by cause, region of birth, maternal age, marital status, human development index and continent of maternal origin was performed. The risk of maternal death was calculated using univariate and multivariate logistic regression analyses, with adjustment for certain variables included in the descriptive analysis. RESULTS: There was a total of 293 maternal deaths and 8,439,324 live births during the study period. The most common cause of maternal death was hypertensive disorders of pregnancy. The average maternal death rate was 3.47 per 100,000 live births. The risk of suffering from this complication was higher for immigrant women from less developed countries. The adjusted effect of maternal HDI score over maternal mortality was OR = 0.976; 95% CI 0.95 - 0.99; p = 0.048; therefore, a decrease of 0.01 in the maternal human development index score significantly increased the risk of this complication by 2.4%. CONCLUSIONS: The results of this study indicate that there are inequalities in maternal mortality according to maternal origin in Spain. The human development index of the country of maternal origin could be a useful tool when estimating the risk of this complication, taking into account the origin of the pregnant woman.

Nonsurgical periodontal treatment in type II diabetics in a middle-income country: a cost-effectiveness analysis.

OBJECTIVES: To evaluate the cost-effectiveness of the nonsurgical periodontal treatment (NSPT) compared with supragingival therapy in type II diabetics with periodontitis. METHODS: A decision tree analysis was used to estimate the costs and health outcomes of two periodontal therapies in a hypothetical cohort of type II diabetics with periodontitis. The analysis was developed from the perspective of a third-party payer at 1 year and 5 years. Probabilities were derived from two systematic reviews. The costs and resource use were validated by a Delphi expert panel. All costs were expressed in USD, using the 25 May 2021 Colombian pesos market exchange rate (USD 1 = COP 3,350). RESULTS: NSPT was a dominant alternative compared with subsidized supragingival therapy in type II diabetics with periodontitis, generating savings of USD 87 and 400, during the first year or up to 5 years, respectively, and improving dental survival from 32 to 69 percent. CONCLUSIONS: NSPT can generate savings by reducing the complications derived from uncontrolled periodontitis and tooth loss.

Survival of Brucella abortus RB51 and S19 Vaccine Strains in Fresh and Ripened Cheeses.

Brucellosis is a zoonotic infection caused by the consumption of contaminated raw milk and dairy products. This study aims to compare survival rates of Brucella abortus RB51 and S19 vaccine strains to that of virulent B. abortus 2308 strain during the manufacture of fresh and ripened cheeses. To do this, we inoculated fresh pasteurized milk with B. abortus RB51, S19, or 2308 at a 6 × 108 colony-forming unit per milliliter concentration during the cheese making process. Cheese was manufactured at room temperature, then, fresh cheeses were conserved at either 4°C or 25°C for 7 days, while ripened cheeses were conserved for 31 days at the same temperatures. We measured B. abortus survival and pH values during different stages of the process. Our results confirm that all three strains can maintain viable cells in both types of cheeses throughout the process. Survival of B. abortus RB51 was 10 times lower than was the survival of the B. abortus S19 and B. abortus 2308 strains in both fresh and ripened cheeses. Our results also suggest that both temperature and pH can condition Brucella survival. In conclusion, B. abortus RB51 and S19 vaccine strains can survive throughout the manufacture and conservation processes of both fresh and ripened cheeses. In turn, this implies a potential health risk if cheeses contaminated with these strains were to be consumed.

Role of Innate and Adaptive Cytokines in the Survival of COVID-19 Patients.

SARS-CoV-2 is a new coronavirus characterized by a high infection and transmission capacity. A significant number of patients develop inadequate immune responses that produce massive releases of cytokines that compromise their survival. Soluble factors are clinically and pathologically relevant in COVID-19 survival but remain only partially characterized. The objective of this work was to simultaneously study 62 circulating soluble factors, including innate and adaptive cytokines and their soluble receptors, chemokines and growth and wound-healing/repair factors, in severe COVID-19 patients who survived compared to those with fatal outcomes. Serum samples were obtained from 286 COVID-19 patients and 40 healthy controls. The 62 circulating soluble factors were quantified using a Luminex Milliplex assay. Results. The patients who survived had decreased levels of the following 30 soluble factors of the 62 studied compared to those with fatal outcomes, therefore, these decreases were observed for cytokines and receptors predominantly produced by the innate immune system-IL-1α, IL-1α, IL-18, IL-15, IL-12p40, IL-6, IL-27, IL-1Ra, IL-1RI, IL-1RII, TNFα, TGFα, IL-10, sRAGE, sTNF-RI and sTNF-RII-for the chemokines IL-8, IP-10, MCP-1, MCP-3, MIG and fractalkine; for the growth factors M-CSF and the soluble receptor sIL2Ra; for the cytokines involved in the adaptive immune system IFNγ, IL-17 and sIL-4R; and for the wound-repair factor FGF2. On the other hand, the patients who survived had elevated levels of the soluble factors TNFß, sCD40L, MDC, RANTES, G-CSF, GM-CSF, EGF, PDGFAA and PDGFABBB compared to those who died. Conclusions. Increases in the circulating levels of the sCD40L cytokine; MDC and RANTES chemokines; the G-CSF and GM-CSF growth factors, EGF, PDGFAA and PDGFABBB; and tissue-repair factors are strongly associated with survival. By contrast, large increases in IL-15, IL-6, IL-18, IL-27 and IL-10; the sIL-1RI, sIL1RII and sTNF-RII receptors; the MCP3, IL-8, MIG and IP-10 chemokines; the M-CSF and sIL-2Ra growth factors; and the wound-healing factor FGF2 favor fatal outcomes of the disease.

Endoscopic view of the intrahepatic biliary ducts by direct per-oral cholangioscopy in a patient with a choledochal cyst.

Sixty year old female with hypertension and crampy abdominal pain episodes. Admitted to hospital (September-2020) by obstructive jaundice. MRCP: biliary dilation due to Todani Ic (fusiform) choledocal cyst (CC), distal sludge. ERCP: normal mucosa prominent papilla; biliary dilation compatible with CC; choledocholithiasis; 8-mm CHD filling defect. Sphincterotomy, removal of stones/sludge, brush-cytology of the filling defect (pathology: atypias). US: dilation resolution (CBD: 6.5 mm).

Does hotel management matter to overcoming the COVID-19 crisis? The Spanish case.

This paper analyses the influence that the initial actions and strategies pursued by hotel managers have on the recovery of occupancy after a crisis such as the COVID-19 pandemic. To do this, a specific survey is carried out on managers of Spanish hotels. The main findings show that labour actions, especially plans for temporary employment regulations, innovation and differentiation strategies, reorientation to closer markets and obtaining information from official sources as a guarantee of their certainty, are the measures that have a greater impact on the possibilities of recovering hotel activity. In addition, government measures that contribute to the improvement of the financial situation of firms can also play a relevant role in hotel recovery.

[The role of metformin in the treatment of dermatological diseases: A narrative review]. / Metformina en el tratamiento de enfermedades dermatológicas: una revisión narrativa.

OBJETIVE: To review and discuss the current evidence of the use of metformin as a therapeutic tool in frequent skin diseases. DESIGN: Original article. Qualitative research. Narrative review. LOCATION: Aragon and Murcia, Spain. PARTICIPANTS: Resident Physicians. Dermatology and Primary Health Care. METHOD: A narrative review has been carried out using the PubMed bibliographic database, being the search date the 27th of January of 2022. RESULTS: Metformin has proven to be effective in the treatment of inflammatory skin diseases such as acne, hidradenitis suppurativa, psoriasis and allergic contact dermatitis. It has also shown antitumor properties regarding basal cell carcinoma, squamous cell carcinoma and melanoma. Additionally, beneficial effects of adjuvant treatment with metformin have been described in patients with basal cell carcinoma receiving photodynamic therapy. In patients with endocrinology-related dermatosis such as hirsutism, acanthosis nigricans and eruptive xanthomas, treatment with metformin has demonstrated therapeutic effectiveness. Topical treatment with metformin has also been useful in the treatment of melasma. Finally, it has been proposed as a drug with anti-aging and wound-healing promoting properties. Severe adverse effects have not been observed for any of the previously described indications, being this a well-tolerated treatment. CONCLUSIONS: Metformin is an effective and safe adjuvant in the therapeutic scheme of various inflammatory dermatoses, skin neoplasms, endocrinology-related dermatosis, melasma, skin aging and wound healing processes.

Replacement and Parallel Simplification of Nonhomologous Proteinases Maintain Venom Phenotypes in Rear-Fanged Snakes.

Novel phenotypes are commonly associated with gene duplications and neofunctionalization, less documented are the cases of phenotypic maintenance through the recruitment of novel genes. Proteolysis is the primary toxic character of many snake venoms, and ADAM metalloproteinases, named snake venom metalloproteinases (SVMPs), are largely recognized as the major effectors of this phenotype. However, by investigating original transcriptomes from 58 species of advanced snakes (Caenophidia) across their phylogeny, we discovered that a different enzyme, matrix metalloproteinase (MMP), is actually the dominant venom component in three tribes (Tachymenini, Xenodontini, and Conophiini) of rear-fanged snakes (Dipsadidae). Proteomic and functional analyses of these venoms further indicate that MMPs are likely playing an "SVMP-like" function in the proteolytic phenotype. A detailed look into the venom-specific sequences revealed a new highly expressed MMP subtype, named snake venom MMP (svMMP), which originated independently on at least three occasions from an endogenous MMP-9. We further show that by losing ancillary noncatalytic domains present in its ancestors, svMMPs followed an evolutionary path toward a simplified structure during their expansion in the genomes, thus paralleling what has been proposed for the evolution of their Viperidae counterparts, the SVMPs. Moreover, we inferred an inverse relationship between the expression of svMMPs and SVMPs along the evolutionary history of Xenodontinae, pointing out that one type of enzyme may be substituting for the other, whereas the general (metallo)proteolytic phenotype is maintained. These results provide rare evidence on how relevant phenotypic traits can be optimized via natural selection on nonhomologous genes, yielding alternate biochemical components.

Baricitinib improves respiratory function in patients treated with corticosteroids for SARS-CoV-2 pneumonia: an observational cohort study.

OBJECTIVES: The Janus kinase (JAK) inhibitor baricitinib may block viral entry into pneumocytes and prevent cytokine storm in patients with SARS-CoV-2 pneumonia. We aimed to assess whether baricitinib improved pulmonary function in patients treated with high-dose corticosteroids for moderate to severe SARS-CoV-2 pneumonia. METHODS: This observational study enrolled patients with moderate to severe SARS-CoV-2 pneumonia [arterial oxygen partial pressure (PaO2)/fraction of inspired oxygen (FiO2) <200 mmHg] who received lopinavir/ritonavir and HCQ plus either corticosteroids (CS group, n = 50) or corticosteroids and baricitinib (BCT-CS group, n = 62). The primary end point was the change in oxygen saturation as measured by pulse oximetry (SpO2)/FiO2 from hospitalization to discharge. Secondary end points included the proportion of patients requiring supplemental oxygen at discharge and 1 month later. Statistics were adjusted by the inverse propensity score weighting (IPSW). RESULTS: A greater improvement in SpO2/FiO2 from hospitalization to discharge was observed in the BCT-CS vs CS group (mean differences adjusted for IPSW, 49; 95% CI: 22, 77; P < 0.001). A higher proportion of patients required supplemental oxygen both at discharge (62.0% vs 25.8%; reduction of the risk by 82%, OR adjusted for IPSW, 0.18; 95% CI: 0.08, 0.43; P < 0.001) and 1 month later (28.0% vs 12.9%, reduction of the risk by 69%, OR adjusted for IPSW, 0.31; 95% CI: 0.11, 0.86; P = 0.024) in the CS vs BCT-CS group. CONCLUSIONS: . In patients with moderate to severe SARS-CoV-2 pneumonia a combination of baricitinib with corticosteroids was associated with greater improvement in pulmonary function when compared with corticosteroids alone. TRIAL REGISTRATION: European Network of Centres for Pharmacoepidemiology and Pharmacovigilance, ENCEPP (EUPAS34966, http://www.encepp.eu/encepp/viewResource.htm? id = 34967).

Social Cognition and Cognitive Decline in Patients with Parkinson's Disease.

Social cognition (SC) comprises an array of cognitive and affective abilities such as social perception, theory of mind, empathy, and social behavior. Previous studies have suggested the existence of deficits in several SC abilities in Parkinson disease (PD), although not unanimously. OBJECTIVE: The aim of this study is to assess the SC construct and to explore its relationship with cognitive state in PD patients. METHOD: We compare 19 PD patients with cognitive decline, 27 cognitively preserved PD patients, and 29 healthy control (HC) individuals in social perception (static and dynamic emotional facial recognition), theory of mind, empathy, and social behavior tasks. We also assess processing speed, executive functions, memory, language, and visuospatial ability. RESULTS: PD patients with cognitive decline perform worse than the other groups in both facial expression recognition tasks and theory of mind. Cognitively preserved PD patients only score worse than HCs in the static facial expression recognition task. We find several significant correlations between each of the SC deficits and diverse cognitive processes. CONCLUSIONS: The results indicate that some components of SC are impaired in PD patients. These problems seem to be related to a global cognitive decline rather than to specific deficits. Considering the importance of these abilities for social interaction, we suggest that SC be included in the assessment protocols in PD.

No antibody response in cutaneous manifestations associated with COVID-19: An observational study of 64 cases with microbiological and clinical characterization.

BACKGROUND: The microbiological diagnosis of skin lesions related to COVID-19 is not well known. OBJECTIVE: Perform a microbiological diagnosis in COVID19-related cutaneous manifestations. METHODS: A cross-sectional study was performed with 64 patients with cutaneous manifestations associated with COVID-19 who underwent serological and nasopharyngeal reverse transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2. RESULTS: Out of the 64 patients, 6 patients had positive RT-PCR, with all of them developing SARS-CoV-2 IgG and 4 of them had positive IgM + IgA. Of the 58 patients with negative RT-PCR, 8 cases had positive IgM + IgA and only one of them had IgG seroconversion. Therefore, the infection was demonstrated in 7 cases (10.9%) and was doubtful in 7 other cases (10.9%) who presented negative RT-PCR and presence of IgA + IgM without subsequent seroconversion of IgG. Fifty patients (78.1%) had negative serological tests. The most frequent cutaneous pattern was pseudo-chilblain (48.4%) followed by maculo-papular pattern (26.6%), urticarial lesions (10.9%), vesicular eruptions (6.3%) and livedoid pattern (4.7%). The maculo-papular pattern showed the highest positivity in RT-PCR (3 cases; 17.6%) and serologies (4 cases; 23.5%). Skin lesions developed after the systemic symptoms in most patients (19 cases; 61.3%). CONCLUSIONS: Microbiological confirmation tests may not be an effective diagnostic technique for COVID-related cutaneous manifestations or that attributed lesions are not related to COVID-19. Confounding factors such as adverse drug reaction, serological cross-reactions with other viruses, the low production of antibodies in asymptomatic or mild forms of COVID-19 or its rapid disappearance, increase diagnostic uncertainty.

Flame Figures in Linear Immunoglobulin A Bullous Dermatosis Secondary to Parvovirus B19 Infection.

ABSTRACT: Flame figures represent a characteristic but nondiagnostic histological finding in eosinophilic dermatoses. Some bullous autoimmune diseases with a predominant eosinophilic infiltrate, such as bullous pemphigoid, pemphigoid gestationis, and pemphigus vegetans, may show them. However, it is rare to find them in predominant neutrophilic bullous dermatoses such as linear immunoglobulin A. We present a 60-year-old man with a history of chronic urticaria, which presented a bullous disease after an acute parvovirus B19 infection. The histological findings showed an exceptional linear immunoglobulin A bullous dermatosis with an eosinophilic infiltrate in the dermis forming "flame figures." The clinical and histopathological findings for this entity may be identical to those of other dermatoses. For this reason, combining these findings with direct immunofluorescence analysis is essential for correct diagnosis of this bullous disease.

A cancer-associated polymorphism in ESCRT-III disrupts the abscission checkpoint and promotes genome instability.

Cytokinetic abscission facilitates the irreversible separation of daughter cells. This process requires the endosomal-sorting complexes required for transport (ESCRT) machinery and is tightly regulated by charged multivesicular body protein 4C (CHMP4C), an ESCRT-III subunit that engages the abscission checkpoint (NoCut) in response to mitotic problems such as persisting chromatin bridges within the midbody. Importantly, a human polymorphism in CHMP4C (rs35094336, CHMP4CT232) increases cancer susceptibility. Here, we explain the structural and functional basis for this cancer association: The CHMP4CT232 allele unwinds the C-terminal helix of CHMP4C, impairs binding to the early-acting ESCRT factor ALIX, and disrupts the abscission checkpoint. Cells expressing CHMP4CT232 exhibit increased levels of DNA damage and are sensitized to several conditions that increase chromosome missegregation, including DNA replication stress, inhibition of the mitotic checkpoint, and loss of p53. Our data demonstrate the biological importance of the abscission checkpoint and suggest that dysregulation of abscission by CHMP4CT232 may synergize with oncogene-induced mitotic stress to promote genomic instability and tumorigenesis.