DNA damage and tissue repair: What we can learn from planaria

Abstract

Faithful renewal of aging and damaged tissues is central to organismal lifespan. Stem cells (SCs) generate the cellular progeny that replenish adult tissues across the body but this task becomes increasingly compromised over time. The age related decline in SC-mediated tissue maintenance is a multifactorial event that commonly affects genome integrity. The presence of DNA damage in SCs that are under continuous demand to divide poses a great risk for age-related disorders such as cancer. However, performing analysis of SCs with genomic instability and the DNA damage response during tissue renewal present significant challenges. Here we introduce an alternative experimental system based on the planaria flatworm Schmidtea mediterranea to address at the organismal level studies intersecting SC-mediated tissue renewal in the presence of genomic instability. Planaria have abundant SCs (neoblasts) that maintain high rates of cellular turnover and a variety of molecular tools have been developed to induce DNA damage and dissect how neoblasts respond to this stressor. S. mediterranea displays high evolutionary conservation of DNA repair mechanisms and signaling pathways regulating adult SCs. We describe genetically induced-DNA damage models and highlight body-wide signals affecting cellular decisions such as survival, proliferation, and death in the presence of genomic instability. We also discuss transcriptomic changes in the DNA damage response during injury repair and propose DNA repair as key component of tissue regeneration. Additional studies using planaria will provide insights about mechanisms regulating survival and growth of cells with DNA damage during tissue renewal and regeneration.

Poly(ADP-Ribose) Polymerase-3 Regulates Regeneration in Planarians

“…Nonetheless, we were able to identify three bona fide human PARP homologs involved in DNA dependent functions. We called these DNA dependent PARP homologs Smed-PARP-1, -2, and -3, which is consistent with recent findings [20,22]. Future studies would be required to define the total number of PARP homologs in S. mediterranea.…”

“…Recently, we have identified that regeneration requires the activation of the DNA damage response (DDR) [20]. Specifically, we showed that Smed-PARP-3 expression peaks between 0 and 3 hours post-amputation (hpa) and it gradually declines over time, which coincides with an increase in expression 6-12 hpa of other DDR proteins including Smed-PARP-1 and -2 [20]. Extending the analysis during regeneration of anterior Figure 4B).…”

“…This analysis revealed that after 15 dpfi the expression of the DNA repair genes tended to decrease but when simultaneous RNAi was performed against the three PARP genes, the expression of Smed-Ku70 and Smed-Rad51 increased ( Figure 3G). We expanded the analysis with immunostaining against the RAD51 protein, which is critical for the repair of DNA double-strand breaks [18][19][20] and found an important increase in the RAD51 signal after 30 dpfi of Smed-PARP-1, -2, and -3 ( Figure 3H,I). The results strongly supported the nuclear function and DNA repair of PARP signaling in planarians.…”

“…Injury-driven cell death and cellular proliferation occur stereotypically within the first few hours [42,44]. Recently, we have identified that regeneration requires the activation of the DNA damage response (DDR) [20]. Specifically, we showed that Smed-PARP-3 expression peaks between 0 and 3 hours post-amputation (hpa) and it gradually declines over time, which coincides with an increase in expression 6-12 hpa of other DDR proteins including Smed-PARP-1 and -2 [20].…”

“…In the case of tissue injury, neoblasts divide, migrate, and their progeny differentiate to rebuild missing or damage tissues [16,17]. Recent work from our group has demonstrated planarians display high evolutionary conservation of DNA damage response and repair (DDR) signaling pathways during tissue homeostasis and regeneration [18][19][20]. Through in silico analysis of regenerating animals, it was determined that the planarian PARP homologue Smed-PARP-3 was expressed independently from other DDR signaling genes during the generic wound response.…”