E2F1, DIAP1, and the presence of a homologous chromosome promote while JNK inhibits radiation-induced loss of heterozygosity in Drosophila melanogaster.

Publisher: Oxford University Press Country of Publication: United States NLM ID: 0374636 Publication Model: Print Cited Medium: Internet ISSN: 1943-2631 (Electronic) Linking ISSN: 00166731 NLM ISO Abbreviation: Genetics Subsets: MEDLINE

Publication: 2021- : [Oxford] : Oxford University Press
Original Publication: Austin, Tex. [etc.]

Chromosomes* ; Drosophila melanogaster*/genetics; Animals ; Humans ; Chromosome Aberrations ; E2F1 Transcription Factor/genetics ; Heterozygote ; Loss of Heterozygosity

Loss of heterozygosity (LOH) can occur when a heterozygous mutant cell loses the remaining wild-type allele to become a homozygous mutant. LOH can have physiological consequences if, for example, the affected gene encodes a tumor suppressor. We used fluorescent reporters to study the mechanisms of LOH induction by X-rays, a type of ionizing radiation (IR), in Drosophila melanogaster larval wing discs. IR is used to treat more than half of patients with cancer, so understanding its effects is of biomedical relevance. Quantitative analysis of IR-induced LOH at different positions between the telomere and the centromere on the X chromosome showed a strong sex dependence and the need for a recombination-proficient homologous chromosome, whereas, paradoxically, position along the chromosome made little difference in LOH incidence. We propose that published data documenting high recombination frequency within centromeric heterochromatin on the X chromosome can explain these data. Using a focused screen, we identified E2F1 as a key promotor of LOH and further testing suggests a mechanism involving its role in cell-cycle regulation. We leveraged the loss of a transcriptional repressor through LOH to express transgenes specifically in cells that have already acquired LOH. This approach identified JNK signaling and apoptosis as key determinants of LOH maintenance. These studies reveal previously unknown mechanisms for the generation and elimination of cells with chromosome aberrations after exposure to IR.
Competing Interests: Conflicts of interest The author(s) declare no conflict of interest.
(© The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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P40 OD018537 United States OD NIH HHS; R35 GM130374 United States GM NIGMS NIH HHS; R35 GM130374 United States NH NIH HHS

Keywords: Drosophila; loss of heterozygosity; radiation

0 (E2F1 protein, human)
0 (E2F1 Transcription Factor)
0 (DIAP1 protein, Drosophila)

Date Created: 20231024 Date Completed: 20240109 Latest Revision: 20241025

20250114

PMC10763536

10.1093/genetics/iyad192

37874851