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Cross-Species Complementation of Nonessential Yeast Genes Establishes Platforms for Testing Inhibitors of Human Proteins.

ABSTRACT: Cross-species complementation can be used to generate humanized yeast, which is a valuable resource with which to model and study human biology. Humanized yeast can be used as an in vivo platform to screen for chemical inhibition of human protein drug targets. To this end, we report the systematic complementation of nonessential yeast genes implicated in chromosome instability (CIN) with their human homologs. We identified 20 human-yeast complementation pairs that are replaceable in 44 assays that test rescue of chemical sensitivity and/or CIN defects. We selected a human-yeast pair (hFEN1/yRAD27), which is frequently overexpressed in cancer and is an anticancer therapeutic target, to perform in vivo inhibitor assays using a humanized yeast cell-based platform. In agreement with published in vitro assays, we demonstrate that HU-based PTPD is a species-specific hFEN1 inhibitor. In contrast, another reported hFEN1 inhibitor, the arylstibonic acid derivative NSC-13755, was determined to have off-target effects resulting in a synthetic lethal phenotype with yRAD27-deficient strains. Our study expands the list of human-yeast complementation pairs to nonessential genes by defining novel cell-based assays that can be utilized as a broad resource to study human drug targets.

SUBMITTER: Hamza A

PROVIDER: S-EPMC7054014 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Cross-Species Complementation of Nonessential Yeast Genes Establishes Platforms for Testing Inhibitors of Human Proteins.

Hamza Akil A Driessen Maureen R M MRM Tammpere Erik E O'Neil Nigel J NJ Hieter Philip P

Genetics 20200114 3

Cross-species complementation can be used to generate humanized yeast, which is a valuable resource with which to model and study human biology. Humanized yeast can be used as an <i>in vivo</i> platform to screen for chemical inhibition of human protein drug targets. To this end, we report the systematic complementation of nonessential yeast genes implicated in chromosome instability (CIN) with their human homologs. We identified 20 human-yeast complementation pairs that are replaceable in 44 as ...[more]

PMID: 31937519

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Project description:BackgroundMen who have sex with men (MSM) who undergo voluntary HIV counseling and testing (VCT) often report condomless anal sexual intercourse, having many sexual partners, and being exposed to risky sexual networks. Limited research has discussed the application of motivational interviewing and convenience referral platforms to facilitate the referral of sexual partners for HIV testing among MSM.ObjectiveThis study aimed to evaluate the effects of VCT referral by sexual partners through social networking platforms and the test results after elicited interviews with MSM; compare the characteristics and risk behaviors among MSM tested without referral, index subjects, and referred sexual partners; and explore unknown sexual affiliations through visualizing and quantifying the social network graph.MethodsThis was a cross-sectional study. Purposeful sampling was used to recruit index subjects from a community HIV screening station frequented by MSM in Taipei City on Friday and Saturday nights. Respondent-driven sampling was used to recruit sexual partners. Partner-elicited interviews were conducted by trained staff before VCT to motivate MSM to become index subjects and refer sexual partners via the Line app, or to disclose the accounts and profiles of sexual partners on relevant social networking platforms. Referred sexual partners received rapid HIV testing, and the recruitment process was repeated until leads were exhausted.ResultsAfter the interviews, 28.2% (75/266) of MSM were successfully persuaded to become index subjects in the first wave, referring 127 sexual partners via the Line app for rapid HIV testing and disclosing 40 sexual partners. The index subjects and tested sexual partners had more sexual partners (F2=3.83, P=.02), more frequent anal intercourse (F2=10.10, P<.001), and higher percentages of those who had not previously received HIV testing (χ21=6.1, P=.047) compared with MSM tested without referrals. The new HIV-seropositivity rate among tested sexual partners was 2.4%, which was higher than the rate in the other 2 groups. The social network analysis revealed the following 4 types of sexual affiliation: chain, Y, star, and complicated. Among the HIV-negative sexual partners, 26.9% (43/160) had sexual affiliations with HIV-positive nodes, and 40% (10/25) were untested sexual partners with a direct sexual affiliation with an HIV-positive node. Four transmission bridges were found in the network graph.ConclusionsPartner-elicited interviews can effectively promote referral for HIV testing and case identification via Line, and can clarify unknown sexual affiliations of MSM to facilitate the development of a tailored prevention program. Social network analysis is needed for an insightful understanding of the different network structures.

Dataset Information

Cross-Species Complementation of Nonessential Yeast Genes Establishes Platforms for Testing Inhibitors of Human Proteins.

Publications

Cross-Species Complementation of Nonessential Yeast Genes Establishes Platforms for Testing Inhibitors of Human Proteins.

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