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Search for chromosomal instability aiding variants reveal naturally occurring kinetochore gene variants that perturb chromosome segregation.
Islam, Asifa; Manjarrez-González, Janeth Catalina; Song, Xinhong; Gore, Trupti; Draviam, Viji M.
Afiliación
  • Islam A; School of Biological and Chemical Sciences, Queen Mary, University of London, London E1 4NS, UK.
  • Manjarrez-González JC; School of Biological and Chemical Sciences, Queen Mary, University of London, London E1 4NS, UK.
  • Song X; School of Biological and Chemical Sciences, Queen Mary, University of London, London E1 4NS, UK.
  • Gore T; School of Biological and Chemical Sciences, Queen Mary, University of London, London E1 4NS, UK.
  • Draviam VM; London Interdisciplinary Doctoral Program, University College London, London, UK.
iScience ; 27(3): 109007, 2024 Mar 15.
Article en En | MEDLINE | ID: mdl-38361632
ABSTRACT
Chromosomal instability (CIN) is a hallmark of cancers, and CIN-promoting mutations are not fully understood. Here, we report 141 chromosomal instability aiding variant (CIVa) candidates by assessing the prevalence of loss-of-function (LoF) variants in 135 chromosome segregation genes from over 150,000 humans. Unexpectedly, we observe both heterozygous and homozygous CIVa in Astrin and SKA3, two evolutionarily conserved kinetochore and microtubule-associated proteins essential for chromosome segregation. To stratify harmful versus harmless variants, we combine live-cell microscopy and controlled protein expression. We find the naturally occurring Astrin p.Q1012∗ variant is harmful as it fails to localize normally and induces chromosome misalignment and missegregation, in a dominant negative manner. In contrast, the Astrin p.L7Qfs∗21 variant generates a shorter isoform that localizes and functions normally, and the SKA3 p.Q70Kfs∗7 variant allows wild-type SKA complex localisation and function, revealing distinct resilience mechanisms that render these variants harmless. Thus, we present a scalable framework to predict and stratify naturally occurring CIVa, and provide insight into resilience mechanisms that compensate for naturally occurring CIVa.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Risk_factors_studies Idioma: En Revista: IScience Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Risk_factors_studies Idioma: En Revista: IScience Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos