Drosophila p53: A master regulator of DNA and tissue damage repair

DNA damage repair and regeneration are important intrinsic regulators of homeostasis during growth and development. Apoptosis, cell proliferation and developmental delay are regulated aspects of each program necessary for monitoring damage, removing irreparable cells and slowing overall animal development as repair is completed. Much is known about how DNA repair is mediated however, little is known about the specific factors used to replace cells lost to this and other tissue damaging events in the growing epithelium.;In addition, we identify a role for dp53 as mediator of a developmental checkpoint following DNA damage. Our results suggest that dp53 is not required for cells to recognize the DNA damaging event and initiate a transient cell cycle arrest. However, following transient arrest, dp53 mutants are unable to delay larval development. We find that this is concomitant with unrepaired DNA lesions and continued development in spite of damage leading to frequently occurring morphological defects and highly increased mortality. Further analysis of dp53 activity and markers for regeneration suggest that dp53 is mediating tissue repair autonomous to the damaged cell and we find that it is sufficient for all aspects of regeneration.;Furthermore, we find that aspects of regeneration are temporally regulated by the concerted and dynamic activation of several growth regulatory pathways in damaged tissue, and that each of these pathways is being regulated by dp53. Finally, our data suggests that onset of tissue damage repair is dependent upon developmental timing of the larvae. As such, dp53-dependent regeneration, initiated too early in development, is detrimental to organ growth and patterning. Admittedly, this may be characteristic of large scale damaging events only. Collectively, our data puts dp53 in a position as master regulator of regeneration following myriad tissue damaging events.;To uncover means by which tissue is mediating aspects of regeneration, we utilized the Drosophila wing imaginal disc. Damaging events were induced by irradiation and over-expression of the pro-death factors, Hid or Rpr (RHG). Strikingly, temporally regulated repair of these damaging events occurs with almost identical responses suggesting that a common repair protein could be regulating both forms of damage. Here, we find that the transcription factor, dp53, which has a well-defined and highly conserved role ensuring the fidelity of replicating DNA during development, is critical for all aspects of regeneration following both kinds of damage. Following irradiation, our data suggests that dp53 is largely activated by the Chk2 kinase, a checkpoint factor, which is activated following DNA damage. Following RHG-induced damage, we find that DNA damage is not induced and Chk2 is dispensable for dp53 activation. Instead, we find that the apical caspase, Dronc is required in a non-apoptotic and dosage-sensitive role for dp53 activation.