p53 is required for female germline stem cell maintenance in P-element hybrid dysgenesis

Abstract

Hybrid dysgenesis is a sterility syndrome resulting from the mobilization of certain transposable elements in the Drosophila germline. Particularly extreme is the hybrid dysgenesis syndrome caused by P-element DNA transposons, in which dysgenic female ovaries often contain few or no germline cells. Those offspring that are produced from dysgenic germlines exhibit high rates of de novo mutation and recombination, implicating transposition-associated DNA damage as the cause of germline loss. However, how this loss occurs, in terms of the particular cellular response that is triggered (cell cycle arrest, senescence, or cell death) remains poorly understood. We demonstrate that two components of the DNA damage response, Checkpoint kinase 2 and its downstream target p53, determine the frequency of ovarian atrophy that is associated with P-element hybrid dysgenesis. We further show that p53 is strongly induced in the germline stem cells (GSCs) of dysgenic females, and is required for their maintenance. Our observations support the critical role for p53 in conferring tolerance of transposable element activity in stem cells.

The Evolution of Small-RNA-Mediated Silencing of an Invading Transposable Element

“…Ectopic recombination events between TE insertions in different genomic locations further produce large structural rearrangements, duplications, and deletions, which are overwhelmingly deleterious (reviewed in Hedges and Deininger, 2007). In addition to these mutational impacts, TE activity itself can have drastic fitness consequences by causing dysgenic sterility, a condition in which germline DNA damage prohibits the production of viable gametes (Bingham et al, 1982;Josefsson et al, 2006;Orsi et al, 2010;Tasnim and Kelleher, 2018). Despite these fitness costs, nearly all genomes are populated by TEs (reviewed in Huang et al, 2012), and…”

Myc plays an important role in Drosophila P-M hybrid dysgenesis to eliminate germline cells with genetic damage

“…The incomplete penetrance suggests that a pathway active in the HD germline, other than MDRG, is partly responsible for the germline-loss phenotype. Compatible with this, mutation in loki/Chk2 partially suppresses the germline-loss phenotype caused by HD 22 . Therefore, it is reasonable to speculate that at least two germline-elimination mechanisms, MDRG and a Chk2-dependent pathway, are responsible for the HD-induced germline-loss phenotype in females.…”

“…Later, in meiotic cells, p53 acts as a downstream effector of loki/Chk2 to induce apoptosis 18,21 . Consistent with their roles in the DNA damage response, loki/Chk2 and p53 also act as modifiers of HDcaused germline loss during oogenesis 22 . Although there is no known link between DNA damage response and Bruno, a regulator of oogenesis [23][24][25] , Bruno activity is also required for the GSC loss phenotype in adult HD females 26 .…”

“…Because it is thought that DNA damage associated with HD causes the germline-loss phenotype 17,40 , one possible mechanism underlying MDRG is that Myc mediates DDR, which induces cell-cycle arrest and apoptosis in the germline 41,42 . In Drosophila oogenesis, when female GSCs and their daughter cells are exposed to DNA damage, loki/Chk2 is required for cell-cycle arrest of GSCs and the loss of these cells 20,22 . Moreover, in meiotic cells, p53 acts downstream of loki/Chk2 to induce apoptosis in response to DNA damage 18,21 .…”

“…Moreover, in meiotic cells, p53 acts downstream of loki/Chk2 to induce apoptosis in response to DNA damage 18,21 . Thus, germline loss during oogenesis in HD females results from GSC loss and meiotic cell apoptosis, which are caused by DNA damage associated with P-element mobilization 22,26 . However, MDRG occurs in HD females at the early third-instar stage ( Figs.…”