RTEL1 maintains genomic stability by suppressing homologous recombination.

Homologous recombination (HR) is an important conserved process for DNA repair and ensures maintenance of genome integrity. Inappropriate HR causes gross chromosomal rearrangements and tumorigenesis in mammals. In yeast, the Srs2 helicase eliminates inappropriate recombination events, but the functional equivalent of Srs2 in higher eukaryotes has been elusive. Here, we identify C. elegans RTEL-1 as a functional analog of Srs2 and describe its vertebrate counterpart, RTEL1, which is required for genome stability and tumor avoidance. We find that rtel-1 mutant worms and RTEL1-depleted human cells share characteristic phenotypes with yeast srs2 mutants: lethality upon deletion of the sgs1/BLM homolog, hyperrecombination, and DNA damage sensitivity. In vitro, purified human RTEL1 antagonizes HR by promoting the disassembly of D loop recombination intermediates in a reaction dependent upon ATP hydrolysis. We propose that loss of HR control after deregulation of RTEL1 may be a critical event that drives genome instability and cancer.

Racial and Ethnic Minorities at the Highest Risk of Uncontrolled Moderate-to-Severe Asthma: A United States Electronic Health Record Analysis.

Purpose: The identification of risk factors associated with uncontrolled moderate-to-severe asthma is important to improve asthma outcomes. Aim of this study was to identify risk factors for uncontrolled asthma in United States cohort using electronic health record (EHR)-derived data. Patients and Methods: In this retrospective real-world study, de-identified data of adolescent and adult patients (≥12 years old) with moderate-to-severe asthma, based on asthma medications within 12 months prior to asthma-related visit (index date), were extracted from the Optum® Humedica EHR. The baseline period was 12 months prior to the index date. Uncontrolled asthma was defined as ≥2 outpatient oral corticosteroid bursts for asthma or ≥2 emergency department visits or ≥1 inpatient visit for asthma. A Cox proportional hazard model was applied. Results: There were 402,403 patients in the EHR between January 1, 2012, and December 31, 2018, who met the inclusion criteria and were analyzed. African American (AA) race (hazard ratio [HR]: 2.08), Medicaid insurance (HR: 1.71), Hispanic ethnicity (HR: 1.34), age of 12 to <18 years (HR 1.20), body mass index of ≥35 kg/m2 (HR: 1.20), and female sex (HR 1.19) were identified as risk factors associated with uncontrolled asthma (P < 0.001). Comorbidities characterized by type 2 inflammation, including a blood eosinophil count of ≥300 cells/µL (as compared with eosinophil <150 cells/µL; HR: 1.40, P < 0.001) and food allergy (HR: 1.31), were associated with a significantly higher risk of uncontrolled asthma; pneumonia was also a comorbidity associated with an increased risk (HR: 1.35) of uncontrolled asthma. Conversely, allergic rhinitis (HR: 0.84) was associated with a significantly lower risk of uncontrolled asthma. Conclusion: This large study demonstrates multiple risk factors for uncontrolled asthma. Of note, AA and Hispanic individuals with Medicaid insurance are at a significantly higher risk of uncontrolled asthma versus their White, non-Hispanic counterparts with commercial insurance.