MEIOSIS&DEVELOPMENT

Control of meiosis and oocyte development by DNA damage checkpoints in Drosophila melanogaster

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 Obiettivo del progetto (Objective)

'DNA damage response (DDR) monitors chromosome status to ensure correct homologous recombination, genomic integrity and chromosome segregation. Thus the effect of DDR activation upon exogenous DNA breaks has been intensely studied. Less is known about the effects of such mechanisms due to endogenous breaks. In multicellular organisms meiosis is a classical example of double strand break (DSB) production and repair occurring concomitantly with gamete development. In Drosophila persistent meiotic DSBs activates the ATR/Mei-41 checkpoint, delays progression through meiosis and causes defects in DNA condensation in the oocyte nucleus. Checkpoint activation has also been linked to decreased levels of the TGFα-like molecule Gurken (GRK), which controls normal eggshell patterning. I used this easy scorable eggshell phenotype in a germ line mosaic screen to identify new genes affecting meiotic progression, DNA condensation and GRK signalling. My work on these mutants challenged the hypothesis that checkpoint activation upon persistent DSBs is exclusively mediated by ATR kinase and instead reveals a more complex network of interactions that link DSB formation, checkpoint activation, meiotic delay, DNA condensation and GRK synthesis. To understand how multicellular organisms monitor chromatin integrity during meiosis and how these surveillance mechanisms affect development I propose the study of the cohesion gene dPds5 in early and late meiosis, the characterization of two rasiRNA genes montecristo and sancho-panza in transposon silencing during oogenesis and the identification of genes downstream of checkpoint pathway mediating eggshell polarity response upon checkpoint activation. I discuss two major new ideas explored in this project: 1. cohesion is required for eggshell polarity, and 2. various branches of the DDR monitor aspects of chromatin independently of DSB.'

Introduzione (Teaser)

The integrity of the eukaryotic genome is maintained through processes that are collectively known as the DNA damage response (DDR). The generation of germ cells during meiosis involves additional mechanisms that are under DDR surveillance.

Descrizione progetto (Article)

The EU-funded 'Control of meiosis and oocyte development by DNA damage checkpoints in Drosophila melanogaster' (MEIOSIS & DEVELOPMENT) project focused on DDR surveillance during meiosis. Project members used the fruit-fly Drosophila melanogaster eggs as a study model.

Their first goal was to investigate the chromatin surveillance during meiosis and germinal vesicle development. Also under investigation was the activation of the DDR late in oogenesis upon deficient functioning of piwi-interacting RNAs (piRNAs). piRNAs are a germ line-specific family of non-coding RNAs.

During the cell cycle, a long prophase I arrest is conserved among animals. Following its condensation into a karyosome, the Drosophila meiotic chromatin appears inert until metaphase I stage of the cell cycle. Researchers discovered novel data about the localisation and co-localisation of the cohesion protein dPDS5 in the germinal vesicle. Based on these results, researchers proposed a new insulator-dependent karyosome model.

piRNAs work to protect the genome against mobilisation of transposable elements. In Drosophila, failure of such protection activates a CHK2-mediated checkpoint in the germ line during mid oogenesis. This checkpoint leads to generation of ribonucleoproteic clumps in the germ cell cytoplasm. To identify piRNA genes, researchers screened a collection of eggshell ventralised mutations using clump markers and identified 24 clump-forming mutants. These discoveries resulted in publications that discuss the efficiency of new screening methods and potential role of these piRNAs in the DDR pathway.

The MEIOSIS & DEVELOPMENT project data has challenged the current hypothesis on checkpoint activations being exclusively controlled by certain limited factors. The general picture based on the project results suggests that it is mediated by a more complex network of interactions.