Chk2 and p53 regulate the transmission of healed chromosomes in the Drosophila male germline
| Autor: | Kent G. Golic, Ho Chen Lin, Simon W. A. Titen, Jayaram Bhandari |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Male
Cancer Research Heredity Cell division lcsh:QH426-470 Mitosis Haploinsufficiency Biology Germline Chromosomes Chromosomal Inheritance Dicentric chromosome Meiosis Genetic Mutation Genetics Cancer Genetics Animals Drosophila Proteins Molecular Biology Genetics (clinical) Ecology Evolution Behavior and Systematics Meiosis II Chromosome Breakage Telomere Cell biology Checkpoint Kinase 2 lcsh:Genetics Meiotic drive Drosophila melanogaster Germ Cells Epistasis Chromosome breakage Tumor Suppressor Protein p53 Gene Function DNA Damage Research Article |
| Zdroj: | PLoS Genetics, Vol 10, Iss 2, p e1004130 (2014) PLoS Genetics |
| ISSN: | 1553-7404 1553-7390 |
| Popis: | When a dicentric chromosome breaks in mitosis, the broken ends cannot be repaired by normal mechanisms that join two broken ends since each end is in a separate daughter cell. However, in the male germline of Drosophila melanogaster, a broken end may be healed by de novo telomere addition. We find that Chk2 (encoded by lok) and P53, major mediators of the DNA damage response, have strong and opposite influences on the transmission of broken-and-healed chromosomes: lok mutants exhibit a large increase in the recovery of healed chromosomes relative to wildtype control males, but p53 mutants show a strong reduction. This contrasts with the soma, where mutations in lok and p53 have the nearly identical effect of allowing survival and proliferation of cells with irreparable DNA damage. Examination of testes revealed a transient depletion of germline cells after dicentric chromosome induction in the wildtype controls, and further showed that P53 is required for the germline to recover. Although lok mutant males transmit healed chromosomes at a high rate, broken chromosome ends can also persist through spermatogonial divisions without healing in lok mutants, giving rise to frequent dicentric bridges in Meiosis II. Cytological and genetic analyses show that spermatid nuclei derived from such meiotic divisions are eliminated during spermiogenesis, resulting in strong meiotic drive. We conclude that the primary responsibility for maintaining genome integrity in the male germline lies with Chk2, and that P53 is required to reconstitute the germline when cells are eliminated owing to unrepaired DNA damage. Author Summary Using the fruitfly as an experimental model system, we produced chromosomes that were broken at one end, and thus lacked the normal telomeric cap. The occurrence of such chromosomes is thought to promote carcinogenesis. A cell's response to such chromosomes is therefore of great interest. In somatic cells the tumor suppressors Chk2 and P53 can induce suicide of cells with such a chromosome and eliminate the danger. In the male germline, though, such chromosomes can be healed by the addition of a new telomere cap, and may then be transmitted to the next generation. We find that Chk2 and P53 regulate healing in the germline, but in seemingly opposite directions. Chk2 functions independently of P53 to eliminate cells with a damaged chromosome, while P53 is required to repopulate the germline after this Chk2-mediated elimination. Cells that carry a broken chromosome continue to divide in Chk2 mutants. We observed that the broken ends of sister chromatids may fuse in meiosis and that the fused chromatids produce a bridge spanning two cells at the second meiotic division. This structure elicits a previously undiscovered mechanism to eliminate sperm derived from such cells, providing an added safeguard to maintain genome integrity through the germline. |
| Databáze: | OpenAIRE |
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