DNA damage-induced Lok/CHK2 activation compromises germline stem cell self-renewal and lineage differentiation

Abstract

Stem cells in adult tissues are constantly exposed to genotoxic stress and also accumulate DNA damage with age. However, it remains largely unknown how DNA damage affects both stem cell selfrenewal and differentiation. In this study, we show that DNA damage retards germline stem cell (GSC) self-renewal and progeny differentiation in a Lok kinase-dependent manner in the Drosophila ovary. Both heatshock-inducible endonuclease I-CreI expression and X-ray irradiation can efficiently introduce double-strand breaks in GSCs and their progeny, resulting in a rapid GSC loss and a GSC progeny differentiation defect. Surprisingly, the elimination of Lok or its kinase activity can almost fully rescue the GSC loss and the progeny differentiation defect caused by DNA damage induced by I-CreI or X-ray. In addition, the reduction in bone morphogenetic protein signaling and Shotgun expression only makes a limited contribution to DNA damage-induced GSC loss. Finally, DNA damage also decreases the expression of the master differentiation factor Bam in a Lok-dependent manner, which helps explain the GSC progeny differentiation defect. Therefore, this study demonstrates, for the first time in vivo, that Lok kinase activation is required for the DNA damage-mediated disruption of adult stem cell self-renewal and lineage differentiation, and might also offer novel insight into how DNA damage causes tissue aging and cancer formation.

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

“…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 .…”

“…This germline-loss phenotype is thought to be caused by DNA damage associated with P-element mobilization 17 . In ovarian germline cells, DNA damage induces cell-cycle arrest and apoptosis via the functions of two DNA damage response (DDR) genes, loki (also known as mnk) encoding checkpoint kinase 2 (Chk2) and p53 [18][19][20][21] . In early oogenesis, loki/Chk2 is required for cell-cycle arrest of the germline stem cells (GSCs) and their daughters in response to DNA damage 18,20 .…”

“…In ovarian germline cells, DNA damage induces cell-cycle arrest and apoptosis via the functions of two DNA damage response (DDR) genes, loki (also known as mnk) encoding checkpoint kinase 2 (Chk2) and p53 [18][19][20][21] . In early oogenesis, loki/Chk2 is required for cell-cycle arrest of the germline stem cells (GSCs) and their daughters in response to DNA damage 18,20 . By contrast, p53 is required for cell-cycle re-entry of GSCs and their maintenance 19,20 .…”

“…In early oogenesis, loki/Chk2 is required for cell-cycle arrest of the germline stem cells (GSCs) and their daughters in response to DNA damage 18,20 . By contrast, p53 is required for cell-cycle re-entry of GSCs and their maintenance 19,20 . Later, in meiotic cells, p53 acts as a downstream effector of loki/Chk2 to induce apoptosis 18,21 .…”

Induction of Chk2 signaling in the germarium is sufficient to cause oogenesis arrest inDrosophila

“…In Drosophila, Chk2-signaling triggered by DNA damage, replication stress or nuclear lamina dysfunction induces GSC loss (Barton et al, 2018;Ma et al, 2016;Molla-Herman et al, 2015). Our previous study showed that removal of Chk2 in vas mutant flies fully restores oogenesis, while progeny embryos succumb to transposon up-regulation and DNA damage (Durdevic et al, 2018).…”