Time-dependent pleiotropic phenotypes are caused by progressive DNA polymerase α deficiency in zebrafish

Lin, A. Y.-S.; Thomas, G. K.; Ang, K.; van Rossum, D. B.; Canfield, V. A.; Cheng, K. C.

doi:10.1101/2020.12.31.425001

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bioRxiv · 10.1101/2020.12.31.425001

Time-dependent pleiotropic phenotypes are caused by progressive DNA polymerase α deficiency in zebrafish

Lin, A. Y.-S.·Thomas, G. K.·Ang, K.·van Rossum, D. B.·Canfield, V. A.·Cheng, K. C.

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Abstract

Pleiotropy caused by single-gene mutations is common and poorly understood. A zebrafish null mutant of DNA polymerase subunit B, huli hutu (hht), evolves a complex pleiotropy associated with DNA damage and S phase arrest across multiple organ systems over 5-7 days, including nuclear atypia, a common cellular feature in human cancers and pre-cancers, in gastrointestinal organs, and nuclear fragmentation in the eye and brain. The pleiotropic pattern of hht phenotypes is explained by progressive loss of wild-type maternal pola2 function in homozygous mutant embryos whose pola2 mRNA becomes undetectable by 24 hours post-fertilization (hpf). Inhibition of DNA synthesis by aphidicolin or hydroxyurea in wild-type embryos from 24 hpf phenocopied the pleiotropic pattern of hht. These results are consistent with a model in which time-sensitive, reduced capacity for DNA synthesis results in cell death in fast-replicating cells, and nuclear atypia in tissues with fewer and larger cells.

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Lin, A. Y.-S., Thomas, G. K., Ang, K., van Rossum, D. B., Canfield, V. A., Cheng, K. C.. 2021-01-03. Time-dependent pleiotropic phenotypes are caused by progressive DNA polymerase α deficiency in zebrafish. https://doi.org/10.1101/2020.12.31.425001

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