Mutation of the Drosophila homologue of the Myb protooncogene causes genomic instability.

in Proceedings of the National Academy of Sciences of the United States of America by J Robert Manak, Nesanet Mitiku, Joseph S Lipsick

TLDR

  • The study found that a gene called Drosophila Myb is important for the process of making copies of DNA during cell division. When this gene is missing, the cells can't make copies of DNA properly, which can lead to problems like cancer. The study also found that this gene provides an important function during cell division that could be targeted for cancer treatment.

Abstract

Vertebrates have three related Myb genes. The c-Myb protooncogene is required for definitive hematopoiesis in mice and when mutated causes leukemias and lymphomas in birds and mammals. The A-Myb gene is required for spermatogenesis and mammary gland proliferation in mice. The ubiquitously expressed B-Myb gene is essential for early embryonic development in mice and is directly regulated by the p16/cyclin D/Rb family/E2F pathway along with many critical S-phase genes. Drosophila has a single Myb gene most closely related to B-Myb. We have isolated two late-larval lethal alleles of Drosophila Myb. Mutant imaginal discs show an increased number of cells arrested in M phase. Mutant mitotic cells display a variety of abnormalities including spindle defects and increased polyploidy and aneuploidy. Remarkably, some mutant cells have an aberrant S- to M-phase transition in which replicating chromosomes undergo premature histone phosphorylation and chromosomal condensation. These results suggest that the absence of Drosophila Myb causes a defect in S phase that may result in M-phase abnormalities. Consistent with a role for Drosophila Myb during S phase, we detected Dm-Myb protein in S-phase nuclei of wild-type mitotic cells as well as endocycling cells, which lack both an M phase and cyclin B expression. Moreover, we found that the Dm-Myb protein is concentrated in regions of S-phase nuclei that are actively undergoing DNA replication. Together these findings imply that Dm-Myb provides an essential nontranscriptional function during chromosomal replication.

Overview

  • The study focuses on the role of Myb genes in vertebrate development and disease. The c-Myb protooncogene is required for definitive hematopoiesis and causes leukemias and lymphomas when mutated. The A-Myb gene is required for spermatogenesis and mammary gland proliferation. The B-Myb gene is essential for early embryonic development and is regulated by the p16/cyclin D/Rb family/E2F pathway. Drosophila has a single Myb gene related to B-Myb. The study aims to investigate the function of Drosophila Myb during S phase and its potential role in M phase abnormalities. The hypothesis being tested is that the absence of Drosophila Myb causes a defect in S phase that may result in M-phase abnormalities. The methodology used for the experiment includes isolating two late-larval lethal alleles of Drosophila Myb, observing mutant imaginal discs and mitotic cells, and detecting Dm-Myb protein in S-phase nuclei. The primary objective of the study is to understand the nontranscriptional function of Dm-Myb during chromosomal replication.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions, specifically the absence of Drosophila Myb versus wild-type conditions. The results show that mutant imaginal discs have an increased number of cells arrested in M phase, and mutant mitotic cells display a variety of abnormalities including spindle defects and increased polyploidy and aneuploidy. Some mutant cells also have an aberrant S- to M-phase transition in which replicating chromosomes undergo premature histone phosphorylation and chromosomal condensation. These findings suggest that the absence of Drosophila Myb causes a defect in S phase that may result in M-phase abnormalities. Consistent with a role for Drosophila Myb during S phase, the study detects Dm-Myb protein in S-phase nuclei of wild-type mitotic cells as well as endocycling cells, which lack both an M phase and cyclin B expression. The Dm-Myb protein is also concentrated in regions of S-phase nuclei that are actively undergoing DNA replication. These results imply that Dm-Myb provides an essential nontranscriptional function during chromosomal replication.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The defect in S phase caused by the absence of Drosophila Myb may contribute to the development of M-phase abnormalities and cancer. The study suggests that Dm-Myb provides an essential nontranscriptional function during chromosomal replication, which could be targeted for cancer therapy. Future research directions could include identifying other genes that regulate S phase and their role in cancer development, studying the interaction between Dm-Myb and other proteins during chromosomal replication, and investigating the potential of Dm-Myb as a therapeutic target for cancer treatment.
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