DAF-16/FOXO and EGL-27/GATA promote developmental growth in response to persistent somatic DNA damage

Abstract

Genome maintenance defects cause complex disease phenotypes characterized by developmental failure, cancer susceptibility, and premature aging. It remains poorly understood how DNA damage responses function during organismal development and maintain tissue functionality when DNA damage accumulates with aging. Here we show that the FoxO transcription factor DAF-16 is activated in response to DNA damage during development while the DNA damage responsiveness of DAF-16 declines with aging. We find that in contrast to its established role in mediating starvation arrest, DAF-16 alleviates DNA damage-induced developmental arrest and even in the absence of DNA repair promotes developmental growth and enhances somatic tissue functionality. We demonstrate that the GATA transcription factor EGL-27 co-regulates DAF-16 target genes in response to DNA damage and together with DAF-16 promotes developmental growth. We propose that EGL-27/GATA activity specifies DAF-16 mediated DNA damage responses to enable developmental progression and to prolong tissue functioning when DNA damage persists.

Mutagenesis of GATA motifs controlling the endoderm regulator elt-2 reveals distinct dominant and secondary cis- regulatory elements

“…The absence of transcriptional activators such as med-1/2, end-3, or end-1 in non-E-cells implies that there may be other GATA-binding transcriptional activators present outside of the nascent endoderm during early embryogenesis (Budovskaya et al, 2008; Gilleard, Shafi, Barry, & McGhee, 1999; Mueller et al, 2014; Murphy et al, 2003). We found that in a minimal 613 bp promoter context, secondary auxiliary HGATAR motif(s) in the 4G region are necessary for producing low-level stochastic transcription (Table 1 613:A4G; Fig 3D).…”

A C. elegans homolog for the UV-hypersensitivity syndrome disease gene UVSSA

“…In C. elegans , the involvement of the two NER sub pathways differs spatially and temporally [19,20,26]. TC-NER is the major repair pathway in transcriptionally active late embryos and early larval stages, whereas GG-NER takes over the role in early embryos and the germ cells, which are highly proliferative.…”

“…TC-NER activity is required for resisting UV-induced DNA lesions during adulthood [20,26,28,29]. We further investigated whether ZK742.2 is involved in the UV-survival of adult worms, which consists almost entirely of post-mitotic cells, except for the germline that undergo mitotic and meiotic cell divisions.…”

Closing the Circle: Stem Cell Rejuvenation and Longevity

“…There is emerging evidence that these pathways are also affected by DNA damage (Niedernhofer et al 2006 ;Mueller et al 2014 ) and might be connected to the immune system (Guo et al 2014 ) and that they control maintenance of pluripotency of stem cells (Bendall et al 2007 ).…”