Abstract
p53 gene family members in humans and other organisms encode a large number of protein isoforms whose functions are largely undefined. Using Drosophila as a model, we find that a p53B isoform is expressed predominantly in the germline where it colocalizes with p53A into subnuclear bodies. It is only p53A, however, that mediates the apoptotic response to ionizing radiation in the germline and soma. In contrast, p53A and p53B are both required for the normal repair of meiotic DNA breaks, an activity that is more crucial when meiotic recombination is defective. We find that in oocytes with persistent DNA breaks p53A is also required to activate a meiotic pachytene checkpoint. Our findings indicate that Drosophila p53 isoforms have DNA lesion and cell type-specific functions, with parallels to the functions of mammalian p53 family members in the genotoxic stress response and oocyte quality control.
Highlights
The p53 protein is best known as a tumor suppressor that plays a central role in the response to DNA damage and other types of stress (Lane and Crawford, 1979; Linzer and Levine, 1979; Levine, 2020). p53 mostly acts as a homotetrameric transcription factor to induce cell cycle arrest, apoptosis, or autophagy, it has other non-transcription factor activities (Levine, 2020)
We found that the Drosophila p53B protein isoform is more highly expressed in the germline where it colocalizes with a shorter p53A isoform in subnuclear bodies
Apoptosis is repressed in meiotic oocytes and endocycling nurse cells, we found that both p53 isoforms are required in these cells for the timely repair of meiotic DNA breaks
Summary
The p53 protein is best known as a tumor suppressor that plays a central role in the response to DNA damage and other types of stress (Lane and Crawford, 1979; Linzer and Levine, 1979; Levine, 2020). p53 mostly acts as a homotetrameric transcription factor to induce cell cycle arrest, apoptosis, or autophagy, it has other non-transcription factor activities (Levine, 2020). Similar to human p53 (TP53), it has a C terminal oligomerization domain (OD), a central DNA-binding domain (DBD) and an N terminal transcriptional activation domain (TAD), and functions as a tetrameric transcription factor (Jin et al, 2000; Ollmann et al, 2000) This single p53 gene expresses four mRNAs that encode three different protein isoforms (Figure 1A; Ingaramo et al, 2018). Other evidence suggests that p53B may regulate tissue regeneration and has a redundant function with p53A to regulate autophagy in response to oxidative stress (Dichtel-D anjoy et al, 2013; Robin et al, 2019) It is largely unknown, why the Drosophila genome encodes a separate p53B isoform and what its array of functions are. We have uncovered that the Drosophila p53A and p53B isoforms have overlapping and distinct functions during oogenesis to protect genome integrity and mediate the meiotic pachytene checkpoint arrest, with parallels to the germline function of mammalian p53 family members in oocyte quality control
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