_:b566103618 . _:b36135712 . _:b566103619 . _:b566103628 . _:b566103629 . _:b566103627 "2"^^ . _:b566103630 . _:b566103631 . _:b566103624 . _:b566103625 . _:b566103626 "2"^^ . _:b566103626 . _:b566103627 . . _:b566103621 . _:b566103637 "2"^^ . . . _:b566103636 "2"^^ . _:b566103639 "2"^^ . _:b36135690 "To identify pathways that respond to DNA damage during development, we developed \u201Cwormpath\u201D, an algorithm that provides a statistical framework to measure enriched genetic or biochemical interactions reported in the C. elegans repository>>11<< (see methods)." . _:b566103638 "2"^^ . . _:b566103652 . _:b566103653 . _:b566103633 "2"^^ . _:b566103601 . _:b566103654 . _:b566103520 . _:b36135735 "All strains were cultured according to standard conditions>>54<<. Strains used were N2 (Bristol; wild type), RB1801 csb-1(ok2335), RB864 xpa-1(ok698), FX03886 xpc-1(tm3886), CB1370 daf-2(e1370), DR1572 daf-2(e1368), DR1565 daf-2(m596), DR26 daf-16(m26), TJ1052 age-1(hx546), DR1309" . _:b566103655 . _:b566103648 . _:b566103649 . _:b566103632 "2"^^ . _:b566103650 . _:b566103651 . . _:b566103660 . _:b36135700 "We also included mutants of age-1, the PI3 kinase acting downstream of DAF->>220<< and additional daf-2 alleles (Figure 2; Suppl." . _:b566103635 "2"^^ . _:b566103645 . _:b566103656 . _:b566103657 . _:b566103634 "2"^^ . _:b566103658 . _:b566103659 . _:b566103652 . _:b566103555 . _:b566103645 "2"^^ . _:b566103541 . . _:b36135691 "factor DAF-16 is activated when inhibitory IIS is alleviated and hypophosphorylated DAF-16 localizes to the nucleus to regulate starvation responses, confer resistance to multiple stress factors and mediate lifespan extension>>12<<-16. To address whether DAF-16 is activated by DNA damage, we monitored DAF-16::GFP localization in vivo16." . _:b566103644 "2"^^ . _:b566103568 . _:b566103647 "2"^^ . _:b36135703 "In contrast to DAF-16, the Nrf-related transcription factor SKN-1, functioning in parallel to DAF-16 to mediate lifespan extension and stress resistance21,>>22<<, was dispensable for the DAF-16 mediated DNA damage tolerance during development (Suppl." . . _:b566103528 . _:b566103609 . _:b566103646 "2"^^ . . _:b566103624 . _:b566103641 "2"^^ . _:b566103635 . _:b566103640 "2"^^ . _:b36135698 . . _:b566103643 "2"^^ . . _:b566103642 "2"^^ . _:b36135692 . . _:b36135710 "The DAF-16 dependent UV-response genes contained 3 significantly enriched sequence matrices that comprise GATA transcription factor recognition sites (Figure 5A), as determined by motif comparison analysis>>28<<. Two motifs contained the DAE element (CTTATCA or TGATAAG) that in addition to its identification as DAF-16 target element29, has also been defined as GATA response element30. Indeed, several GATA factors are required for the longevity of" . _:b566103590 . _:b566103653 "2"^^ . _:b36135693 . _:b566103575 . _:b36135734 "experimental procedures" . _:b566103652 "2"^^ . _:b36135694 . _:b566103655 "2"^^ . _:b36135695 . _:b566103654 "2"^^ . . _:b36135688 . _:b566103519 "8"^^ . . _:b566103649 "2"^^ . _:b566103655 . . _:b36135689 . _:b36135723 "In both cases DAF-16 confers general stress resistance as observed upon starvation, heat, reactive oxygen species, and UV12,>>14<<,16,40,41 likely through the induction of DBE-controlled genes." . _:b566103648 "2"^^ . _:b36135690 . . . _:b36135723 . . _:b566103651 "2"^^ . _:b566103659 . _:b36135691 . . _:b566103650 "2"^^ . _:b36135700 . _:b36135701 . . . _:b566103660 "2"^^ . _:b36135702 . . _:b566103612 . _:b36135703 . . _:b566103525 "4"^^ . _:b566103546 . _:b36135696 . _:b566103650 . _:b566103524 "5"^^ . _:b36135692 "To address whether DAF-16 is activated by DNA damage, we monitored DAF-16::GFP localization in vivo>>16<<. While in the absence of UV DAF-16::GFP was completely cytoplasmic, we observed a transient nuclear localization upon UV treatment during larval stages (L1 larvae Figure 1C; L3 larvae Suppl. Figure 1G). DAF-16 showed nearly complete and" . _:b566103657 "2"^^ . _:b36135697 . _:b566103639 . _:b566103527 "4"^^ . . _:b566103656 "2"^^ . . . _:b36135698 . _:b566103630 . _:b36135721 . _:b566103526 "4"^^ . _:b566103659 "2"^^ . _:b36135699 . . . _:b566103584 . _:b566103658 "2"^^ . _:b36135708 . _:b566103522 . _:b566103572 . _:b566103544 . _:b36135709 . _:b566103520 "8"^^ . _:b566103523 "5"^^ . _:b36135710 . _:b566103521 "7"^^ . . . _:b566103522 "5"^^ . . _:b36135711 . _:b566103651 . _:b566103533 "4"^^ . _:b36135704 . _:b566103532 "4"^^ . . _:b36135705 . _:b566103535 "3"^^ . _:b566103519 . . _:b36135706 . _:b566103534 "4"^^ . _:b36135707 . _:b36135728 . _:b36135713 . _:b566103529 "4"^^ . _:b566103557 . _:b36135716 . _:b36135717 "In accordance with our observations, reduced IIS has been observed in progeroid mice lacking Sirtuin >>636<<, or the NER factors Ercc1 or Csb and Xpa37,38. We previously showed that persistent DNA damage that leads to RNAPII stalling, the culprit of TC-NER deficiencies, evokes IIS attenuation in mammalian cells39." . _:b566103528 "4"^^ . _:b566103582 . _:b36135704 . _:b36135717 . _:b566103531 "4"^^ . _:b36135718 . _:b566103530 "4"^^ . _:b566103634 . . _:b36135719 . _:b566103541 "3"^^ . _:b566103525 . _:b566103640 . _:b36135712 . _:b566103540 "3"^^ . . _:b566103524 . _:b36135712 "Indeed, several GATA factors are required for the longevity of daf-2 mutants>>30<<-32. To investigate the function of GATA factors in the developmental response to UV irradiation, we analysed elt-3, elt-4, elt-6, elt-7, egl-27, end-1, end-3, med-1, and med-2 mutants. Specifically egl-27 mutants exhibited a strongly" . _:b36135713 . _:b566103543 "3"^^ . _:b566103527 . . _:b566103542 "3"^^ . _:b36135714 . _:b566103526 . _:b566103550 . _:b36135715 . _:b566103537 "3"^^ . _:b566103521 . . _:b36135724 . _:b566103629 . _:b566103536 "3"^^ . _:b36135739 . _:b36135732 "Once embryogenesis ensues, cellular DNA damage checkpoints are switched off>>7<<. In the subsequent larval development the IIS response might force growth even when DNA damage persists thus ensuring the maximal usage of previously invested maternal resources." . _:b566103520 . _:b566103594 . _:b36135725 . _:b566103539 "3"^^ . _:b566103536 . _:b566103523 . _:b36135726 . _:b566103538 "3"^^ . _:b566103522 . . _:b36135727 . _:b566103549 "3"^^ . _:b566103533 . _:b36135704 "In adult animals, UV damage leads to lifespan reduction in xpa-1 mutant worms>>23<<. While xpa-1 mutants showed a dramatic reduction in pharyngeal pumping and motility following UV treatment, the xpa-1;daf-2 double mutants maintained tissue functionality (Figure 3C, D; Suppl. Figure 4A) and their lifespan was" . _:b36135720 . _:b566103548 "3"^^ . _:b566103532 . _:b36135721 . _:b566103551 "3"^^ . _:b36135699 . _:b566103535 . _:b36135722 . _:b566103550 "3"^^ . _:b566103534 . _:b36135723 . _:b566103545 "3"^^ . _:b566103529 . _:b566103583 . _:b36135732 . _:b566103544 "3"^^ . . _:b36135696 . _:b566103528 . _:b36135733 . _:b566103547 "3"^^ . _:b566103531 . _:b566103546 "3"^^ . _:b36135734 . _:b566103530 . _:b36135735 . _:b566103541 . _:b36135728 . _:b36135691 . . _:b566103540 . _:b36135729 . _:b566103543 . _:b36135730 . _:b566103542 . _:b36135689 "These data suggest that rather than functioning during different developmental periods as previously thought>>9<<, already during larval development the two NER branches in C. elegans show specific requirements of GG-NER in germ cells and of TC-NER in somatic tissues." . _:b36135731 . _:b566103537 . _:b566103577 . _:b36135740 . . _:b566103536 . . _:b36135741 . . _:b566103539 . _:b36135742 . _:b566103607 . _:b36135737 "We searched either 600 or 1000 base pairs upstream of the start codon, for TGTTTAC the canonical DAF-16 Binding Element (DBE) motif>>56<<; CTTATCA the predicted DAF-16 Associated Element (DAE)26; NTTCNNGAANNTTCN, NTTCNNGAAN(N)5NGAAN and NTTCN(N)5NTTCN(N)5NGAAN the Heat Shock Elements (HSE)57; WWTRTCAT the SKN-1 binding motif22 and CATATG an Heme-responsive element58." . _:b566103538 . _:b36135743 . _:b566103549 . _:b36135736 . _:b36135712 . . _:b566103548 . _:b36135730 . _:b36135737 . _:b566103551 . _:b36135738 . . _:b566103571 . _:b566103550 . _:b36135739 . _:b566103526 . . _:b566103633 . _:b566103545 . . _:b566103544 . _:b36135709 . _:b36135738 . _:b566103547 . _:b566103619 . _:b566103551 . _:b566103546 . _:b566103547 . _:b36135707 "Systematic analysis of putative promoter elements employing the RSAT software>>25<< revealed a highly significant enrichment of the DAF-16 associated element (DAE)26 within the UV-induced genes, while starvation induced genes showed highly significant enrichment of the DAF-16 binding element (DBE) (Table 1)." . _:b36135728 . . . . . _:b36135705 . . _:b566103531 . . _:b566103543 . _:b566103599 . _:b36135710 . . . . _:b566103574 . _:b36135702 "In contrast to DAF-16, the Nrf-related transcription factor SKN-1, functioning in parallel to DAF-16 to mediate lifespan extension and stress resistance>>21<<,22, was dispensable for the DAF-16 mediated DNA damage tolerance during development (Suppl." . . . _:b36135697 . . . . . _:b36135729 . . _:b36135701 . . _:b566103519 . . _:b36135724 "In both cases DAF-16 confers general stress resistance as observed upon starvation, heat, reactive oxygen species, and UV12,14,>>16<<,40,41 likely through the induction of DBE-controlled genes." . . . . . . . _:b566103540 . _:b566103541 . _:b566103542 . _:b566103543 . . _:b566103536 . _:b566103537 . _:b566103538 . _:b566103539 . _:b566103548 . _:b566103549 . _:b566103550 . _:b36135741 "motif56; CTTATCA the predicted DAF-16 Associated Element (DAE)26; NTTCNNGAANNTTCN, NTTCNNGAAN(N)5NGAAN and NTTCN(N)5NTTCN(N)5NGAAN the Heat Shock Elements (HSE)57; WWTRTCAT the SKN-1 binding motif22 and CATATG an Heme-responsive element>>58<<. Transcription factor sites search was performed using the DNA-pattern matching tool of regulatory sequence analysis tools RSAT software (http:" . _:b36135708 . _:b566103551 . _:b566103544 . _:b566103545 . _:b566103546 . _:b566103576 . _:b566103547 . _:b566103524 . _:b566103525 . _:b566103526 . _:b566103527 . _:b566103520 . _:b566103521 . _:b566103522 . _:b566103523 . _:b566103532 . _:b566103533 . _:b36135725 "In both cases DAF-16 confers general stress resistance as observed upon starvation, heat, reactive oxygen species, and UV12,14,16,>>40<<,41 likely through the induction of DBE-controlled genes." . _:b566103534 . _:b566103535 . _:b566103528 . _:b566103529 . _:b566103530 . _:b566103531 . _:b566103606 . . . . . . _:b36135743 "A truncation of hEPS15L1 [1-225] was used as a negative control>>59<<." . _:b566103519 . _:b566103561 . _:b36135722 . _:b36135706 "In agreement with previous gene expression data>>24<<, we observed a strong transcriptional response to starvation (Table S4)." . _:b36135743 . _:b566103581 . . . _:b36135736 . _:b566103622 . . _:b36135733 "Developmental timing and lifespan are intricately linked as slowly developing organisms require a longer lifespan for successful reproduction>>51<<. The IIS response to DNA damage might thus also adapt to co-regulate developmental timing and lifespan in response to persistent DNA damage." . _:b566103632 . _:b36135720 . _:b36135720 "We previously showed that persistent DNA damage that leads to RNAPII stalling, the culprit of TC-NER deficiencies, evokes IIS attenuation in mammalian cells>>39<<. We now for the first time reveal the physiological function of IIS response to persistent DNA damage. We show that genetic IIS attenuation leads to suppression of the DNA damage induced somatic growth arrest through activation of DAF-16." . _:b36135690 . . _:b566103649 . . _:b36135726 . _:b36135691 . . . _:b36135699 "The canonical temperature sensitive daf-2(e1370) allele shows a slightly delayed but otherwise unperturbed development at the semi-permissive temperature of 20 \u00B0C (Figure 2, untreated)>>18<<. We also included mutants of age-1, the PI3 kinase acting downstream of DAF-220 and additional daf-2 alleles (Figure 2; Suppl. Figure 2D). Strikingly, 48h post UV-treatment a significantly higher number of daf-2 or age-1 mutant animals" . . _:b36135715 "Activation of the IIS effector DAF-16 was previously observed in response to various stressors including starvation, heat, and juglone but not UV>>16<<. In contrast to previous studies that used short wavelength UVC, which is unlikely to penetrate throughout the worm\u2019s tissues, we observed DAF-16 activation upon irradiation with more deeply penetrating and physiologically more relevant" . _:b566103641 . _:b36135696 "The function of DAF-16 in mediating lifespan extension and stress resistance has become evident through analysis of mutations in the insulin/IGF-1 receptor daf-2 that lead to constitutive activation of DAF-1614,15,>>18<<. Complete loss-of-function of daf-2 results in permanent L1 arrest13 and strong loss-of-function alleles in permanent dauer arrest19." . _:b36135709 "SKN-1, previously implied in the starvation response>>27<<, was dispensable for this effect (Suppl." . _:b36135695 . . _:b36135722 "In both cases DAF-16 confers general stress resistance as observed upon starvation, heat, reactive oxygen species, and UV>>12<<,14,16,40,41 likely through the induction of DBE-controlled genes." . _:b36135711 . . . _:b566103587 . . _:b36135712 . _:b36135702 . _:b36135706 . _:b566103615 . _:b566103660 . _:b36135718 "In accordance with our observations, reduced IIS has been observed in progeroid mice lacking Sirtuin 636, or the NER factors Ercc1 or Csb and Xpa>>37<<,38. We previously showed that persistent DNA damage that leads to RNAPII stalling, the culprit of TC-NER deficiencies, evokes IIS attenuation in mammalian cells39." . _:b36135742 . _:b36135741 . _:b566103569 . . _:b36135697 "Complete loss-of-function of daf-2 results in permanent L1 arrest>>13<< and strong loss-of-function alleles in permanent dauer arrest19." . . _:b36135691 . . _:b36135738 "We searched either 600 or 1000 base pairs upstream of the start codon, for TGTTTAC the canonical DAF-16 Binding Element (DBE) motif56; CTTATCA the predicted DAF-16 Associated Element (DAE)>>26<<; NTTCNNGAANNTTCN, NTTCNNGAAN(N)5NGAAN and NTTCN(N)5NTTCN(N)5NGAAN the Heat Shock Elements (HSE)57; WWTRTCAT the SKN-1 binding motif22 and CATATG an Heme-responsive element58." . . . . . . _:b566103593 . _:b36135729 "The human EGL-27 homolog metastasis tumour antigen 1 (MTA1) is associated with aggressiveness of various tumour types>>46<<,47 and is required for an efficient G2/M arrest following DNA damage48." . _:b566103608 . _:b566103618 . _:b566103657 . . . _:b36135705 "To assess the role of DAF-16 in developmental gene regulation, we contrasted the gene expression changes upon UV treatment with those upon starvation, where DAF-16 has previously been shown to mediate L1 arrest>>13<<. In agreement with previous gene expression data24, we observed a strong transcriptional response to starvation (Table S4)." . _:b566103557 . _:b566103602 . _:b566103556 . _:b566103559 . _:b36135740 "canonical DAF-16 Binding Element (DBE) motif56; CTTATCA the predicted DAF-16 Associated Element (DAE)26; NTTCNNGAANNTTCN, NTTCNNGAAN(N)5NGAAN and NTTCN(N)5NTTCN(N)5NGAAN the Heat Shock Elements (HSE)57; WWTRTCAT the SKN-1 binding motif>>22<< and CATATG an Heme-responsive element58. Transcription factor sites search was performed using the DNA-pattern matching tool of regulatory sequence analysis tools RSAT software (http:" . _:b566103558 . _:b36135739 "of the start codon, for TGTTTAC the canonical DAF-16 Binding Element (DBE) motif56; CTTATCA the predicted DAF-16 Associated Element (DAE)26; NTTCNNGAANNTTCN, NTTCNNGAAN(N)5NGAAN and NTTCN(N)5NTTCN(N)5NGAAN the Heat Shock Elements (HSE)>>57<<; WWTRTCAT the SKN-1 binding motif22 and CATATG an Heme-responsive element58. Transcription factor sites search was performed using the DNA-pattern matching tool of regulatory sequence analysis tools RSAT software (http:" . _:b566103553 . . _:b566103552 . _:b36135701 "of activated DAF-16 to override the DNA damage-induced developmental arrest comprises a previously unknown function of DAF-16 that contrasts its role in starvation arrest, in which activated DAF-16 mediates the developmental stalling>>13<<." . _:b566103555 . _:b566103554 . . _:b566103565 . _:b566103564 . . _:b566103567 . _:b566103653 . _:b566103566 . _:b566103561 . _:b566103573 . _:b566103554 . . _:b566103560 . _:b566103556 . _:b566103597 . _:b566103563 . _:b36135714 "discussion" . _:b566103562 . . _:b566103573 . _:b566103525 . _:b566103567 . . _:b566103572 . _:b36135725 . _:b566103600 . . _:b566103575 . . _:b36135693 "The kinetics of DAF-16 translocation within several hours following UV exposure is indeed consistent with the kinetics of RNAPII dependent detection of transcription-blocking lesions>>17<<." . _:b36135707 . _:b566103574 . _:b566103535 . _:b566103569 . _:b566103568 . _:b566103549 . _:b566103539 . _:b36135730 "The human EGL-27 homolog metastasis tumour antigen 1 (MTA1) is associated with aggressiveness of various tumour types46,>>47<< and is required for an efficient G2/M arrest following DNA damage48." . _:b566103571 . _:b566103548 . _:b566103647 . . _:b566103570 . _:b566103581 . . _:b566103580 . _:b566103628 . _:b566103583 . _:b566103582 . _:b36135717 . . _:b566103598 . _:b566103577 . . . _:b566103576 . _:b566103579 . _:b566103578 . _:b566103589 . . _:b36135703 . . _:b566103588 . . _:b566103591 . _:b566103586 . _:b566103631 . . _:b566103559 . _:b566103590 . _:b566103545 . _:b566103585 . . . _:b566103654 . . _:b566103584 . _:b566103587 . _:b566103586 . _:b566103610 . . _:b566103597 . . . _:b566103596 . . . _:b36135716 "Natural sampling experiments identified developing C. elegans larvae outside of the starvation arrest exclusively on decaying fruits and fresh compost heaps>>34<<. With a yearly average irradiation in central Europe of 4mJ/cm2 UVB per minute, with significantly higher peaks during summer and at higher altitudes35, the UV response mechanisms are thus likely to play an important role in the natural" . _:b566103580 . _:b566103599 . _:b566103598 . . _:b36135737 . . _:b566103593 . "10.1038%2Fncb3071" . _:b566103592 . . _:b566103595 . _:b566103636 . _:b566103594 . . _:b566103605 . _:b36135736 "For data analysis, the second derivative maximum method was applied, and induction of target cDNA was calculated according to Pfaffl>>55<<: [Etarget\u0394CP(cDNAuntreated-cDNAtreated)target]/[Econtrol\u0394CP(cDNAuntreated-cDNAtreated)control]." . . _:b566103614 . _:b566103604 . _:b566103607 . _:b566103606 . . _:b566103558 . _:b566103601 . _:b36135713 "egl-27 mutants showed enhanced sensitivity to oxidative damage (which among others also imposes transcription blocking lesions>>33<<) that was further aggravated in daf-16;egl-27 double mutants (Suppl." . . _:b566103600 . . . _:b566103603 . . _:b566103527 . _:b566103602 . . . _:b566103613 . _:b36135724 . . _:b566103585 . _:b566103612 . _:b566103578 . _:b36135695 "The function of DAF-16 in mediating lifespan extension and stress resistance has become evident through analysis of mutations in the insulin/IGF-1 receptor daf-2 that lead to constitutive activation of DAF-1614,>>15<<,18. Complete loss-of-function of daf-2 results in permanent L1 arrest13 and strong loss-of-function alleles in permanent dauer arrest19." . _:b566103615 . _:b36135734 _:b36135740 . _:b566103614 . _:b36135734 _:b36135741 . _:b36135734 _:b36135742 . _:b36135734 _:b36135743 . _:b36135734 _:b36135736 . _:b566103609 . _:b36135734 _:b36135737 . _:b36135734 _:b36135738 . _:b36135734 _:b36135739 . _:b566103608 . . _:b36135715 . _:b36135734 _:b36135735 . _:b566103557 "3"^^ . _:b566103611 . _:b566103540 . _:b566103589 . _:b36135711 "Two motifs contained the DAE element (CTTATCA or TGATAAG) that in addition to its identification as DAF-16 target element29, has also been defined as GATA response element>>30<<. Indeed, several GATA factors are required for the longevity of daf-2 mutants30-32. To investigate the function of GATA factors in the developmental response to UV irradiation, we analysed elt-3, elt-4, elt-6, elt-7, egl-27, end-1, end-3," . . _:b566103596 . _:b566103610 . _:b566103556 "3"^^ . _:b566103559 "2"^^ . _:b566103552 . _:b566103621 . . _:b566103595 . _:b566103558 "2"^^ . _:b566103620 . _:b566103638 . _:b566103560 . . _:b566103553 "3"^^ . _:b566103623 . _:b36135721 "This previously unknown function contrasts the established role of DAF-16 in response to starvation>>13<<. In both cases DAF-16 confers general stress resistance as observed upon starvation, heat, reactive oxygen species, and UV12,14,16,40,41 likely through the induction of DBE-controlled genes. Specifically in response to DNA damage, DAF-16" . _:b566103552 "3"^^ . _:b566103622 . _:b566103625 . . _:b566103555 "3"^^ . _:b566103617 . . _:b566103554 "3"^^ . _:b566103616 . _:b566103627 . . _:b566103565 "2"^^ . _:b566103619 . _:b566103592 . . _:b566103613 . _:b566103564 "2"^^ . _:b566103618 . "PMC0" . . _:b566103567 "2"^^ . _:b566103629 . _:b566103566 "2"^^ . _:b36135716 . _:b566103628 . . _:b566103616 . _:b566103644 . _:b566103561 "2"^^ . _:b566103631 . . _:b36135714 _:b36135724 . _:b566103560 "2"^^ . _:b36135714 _:b36135725 . _:b566103630 . _:b36135714 _:b36135726 . _:b36135740 . _:b566103529 . _:b36135714 _:b36135727 . _:b36135714 _:b36135720 . _:b566103563 "2"^^ . _:b36135714 _:b36135721 . _:b566103625 . . . _:b36135714 _:b36135722 . _:b36135714 _:b36135723 . _:b36135714 _:b36135716 . _:b566103562 "2"^^ . _:b36135714 _:b36135717 . _:b566103624 . _:b566103565 . _:b36135714 _:b36135718 . _:b36135714 _:b36135719 . _:b566103530 . _:b566103573 "2"^^ . _:b566103627 . _:b36135727 "Conceptually consistent with a dual function, the activation of the mammalian DAF-16 homolog also results in very contrasting consequences as FoxO acts tumour suppressive in solid tumours but oncogenic in an acute myeloid lymphoma>>42<<. It will be highly interesting to evaluate whether context-dependent transcription co-factors determine the distinct outcomes of FoxO activity." . _:b36135714 _:b36135715 . _:b566103533 . . _:b566103572 "2"^^ . _:b566103626 . _:b566103575 "2"^^ . _:b566103637 . _:b36135714 _:b36135732 . _:b566103574 "2"^^ . _:b36135688 . _:b36135714 _:b36135733 . _:b566103636 . . . _:b36135714 _:b36135728 . _:b566103569 "2"^^ . _:b36135714 _:b36135729 . _:b566103639 . _:b36135714 _:b36135730 . _:b36135714 _:b36135731 . . _:b566103568 "2"^^ . . _:b566103638 . _:b36135718 . . _:b566103658 . _:b566103571 "2"^^ . _:b566103633 . _:b566103570 "2"^^ . _:b566103632 . _:b36135691 . _:b566103581 "2"^^ . _:b566103635 . _:b36135732 . _:b566103580 "2"^^ . _:b566103634 . _:b36135731 "capacity, which would require adaptations in multiple genome maintenance systems and in case of NER involve multi-protein complexes with abundant base line levels that are assembled upon damage recognition with highly complex dynamics>>49<<." . _:b36135714 . _:b566103583 "2"^^ . _:b566103542 . _:b566103645 . _:b566103566 . _:b36135692 . _:b36135688 "results" . _:b566103582 "2"^^ . _:b566103644 . _:b566103646 . _:b566103577 "2"^^ . _:b36135693 . _:b566103564 . _:b566103647 . _:b36135734 . . . _:b566103576 "2"^^ . _:b566103646 . . _:b566103579 "2"^^ . _:b566103603 . _:b566103641 . _:b566103532 . _:b566103578 "2"^^ . _:b566103640 . _:b566103589 "2"^^ . _:b566103643 . _:b566103538 . _:b566103611 . _:b566103588 "2"^^ . _:b566103642 . _:b566103537 . . . _:b566103591 "2"^^ . _:b566103642 . _:b566103653 . _:b566103590 "2"^^ . _:b566103652 . _:b566103604 . . _:b566103585 "2"^^ . _:b566103655 . _:b566103524 . _:b36135742 "be/rsat/)>>25<<. The results given are the total percentage of matches for each cluster, in both strands of the sequence." . _:b566103584 "2"^^ . _:b566103654 . _:b566103605 . _:b566103587 "2"^^ . _:b566103649 . . _:b566103586 "2"^^ . _:b566103643 . _:b566103648 . . _:b566103597 "2"^^ . _:b566103651 . _:b36135700 . _:b566103596 "2"^^ . _:b566103650 . _:b566103521 . _:b566103599 "2"^^ . _:b566103534 . _:b36135728 . . _:b566103598 "2"^^ . _:b566103660 . _:b566103593 "2"^^ . . _:b566103592 "2"^^ . . . _:b566103637 . _:b566103595 "2"^^ . _:b566103657 . _:b36135688 _:b36135692 . _:b566103594 "2"^^ . _:b36135688 _:b36135693 . _:b566103656 . _:b36135688 _:b36135694 . _:b36135728 "egl-27 has previously been found to regulate cell polarity, migration, and embryonic patterning redundantly with the related GATA factor egr->>143<<-45. The human EGL-27 homolog metastasis tumour antigen 1 (MTA1) is associated with aggressiveness of various tumour types46,47 and is required for an efficient G2/M arrest following DNA damage48. It will be highly interesting to" . _:b36135688 _:b36135695 . . _:b566103605 "2"^^ . _:b36135688 _:b36135689 . _:b566103659 . _:b36135688 _:b36135690 . _:b36135688 _:b36135691 . _:b36135731 . _:b36135688 _:b36135700 . _:b566103604 "2"^^ . _:b36135688 _:b36135701 . _:b566103658 . _:b36135688 _:b36135702 . _:b36135688 _:b36135703 . _:b36135688 _:b36135696 . _:b566103607 "2"^^ . . _:b36135688 _:b36135697 . _:b36135688 _:b36135698 . _:b36135688 _:b36135699 . . _:b36135688 _:b36135708 . _:b566103606 "2"^^ . _:b36135688 _:b36135709 . _:b36135688 _:b36135710 . _:b36135688 _:b36135711 . _:b36135688 _:b36135704 . _:b566103601 "2"^^ . _:b36135688 _:b36135705 . _:b36135688 _:b36135706 . _:b36135688 _:b36135707 . . _:b566103600 "2"^^ . _:b36135735 . . . _:b36135733 . _:b36135688 _:b36135712 . _:b566103603 "2"^^ . . _:b36135688 _:b36135713 . . . _:b566103602 "2"^^ . _:b566103572 . _:b36135719 . _:b566103620 . _:b566103573 . _:b566103613 "2"^^ . _:b566103574 . _:b566103575 . _:b566103568 . . _:b566103612 "2"^^ . _:b566103569 . _:b566103570 . _:b566103562 . _:b566103571 . _:b566103580 . _:b566103615 "2"^^ . _:b566103581 . . _:b566103582 . _:b566103583 . . _:b36135708 "Systematic analysis of putative promoter elements employing the RSAT software25 revealed a highly significant enrichment of the DAF-16 associated element (DAE)>>26<< within the UV-induced genes, while starvation induced genes showed highly significant enrichment of the DAF-16 binding element (DBE) (Table 1)." . _:b36135694 "The function of DAF-16 in mediating lifespan extension and stress resistance has become evident through analysis of mutations in the insulin/IGF-1 receptor daf-2 that lead to constitutive activation of DAF->>1614<<,15,18. Complete loss-of-function of daf-2 results in permanent L1 arrest13 and strong loss-of-function alleles in permanent dauer arrest19." . _:b566103576 . _:b566103614 "2"^^ . _:b566103577 . _:b566103570 . . _:b566103578 . _:b566103579 . _:b566103556 . _:b566103609 "2"^^ . _:b566103557 . _:b566103558 . . _:b36135698 "Complete loss-of-function of daf-2 results in permanent L1 arrest13 and strong loss-of-function alleles in permanent dauer arrest>>19<<. The canonical temperature sensitive daf-2(e1370) allele shows a slightly delayed but otherwise unperturbed development at the semi-permissive temperature of 20 \u00B0C (Figure 2, untreated)18. We also included mutants of age-1, the PI3 kinase" . _:b566103559 . _:b566103552 . _:b36135689 . _:b566103608 "2"^^ . _:b566103553 . _:b566103554 . _:b566103555 . _:b566103523 . _:b566103564 . _:b566103611 "2"^^ . _:b566103565 . _:b566103566 . _:b566103626 . _:b566103563 . _:b566103567 . _:b566103553 . _:b566103560 . _:b566103610 "2"^^ . . _:b566103561 . _:b566103562 . . _:b566103563 . _:b566103623 . _:b566103604 . _:b566103621 "2"^^ . _:b36135727 . _:b566103605 . _:b566103617 . _:b566103606 . _:b566103607 . _:b566103600 . _:b566103620 "2"^^ . _:b566103601 . _:b566103602 . _:b566103603 . _:b566103648 . _:b566103612 . _:b566103613 . _:b566103623 "2"^^ . _:b566103591 . . _:b566103614 . _:b566103615 . . _:b566103608 . _:b566103622 "2"^^ . _:b566103609 . _:b566103610 . _:b566103611 . _:b566103588 . _:b566103617 "2"^^ . _:b566103589 . _:b566103590 . _:b566103591 . _:b566103584 . _:b566103616 "2"^^ . _:b566103585 . _:b566103586 . _:b566103587 . _:b566103656 . _:b566103596 . _:b36135691 . _:b566103619 "2"^^ . _:b566103597 . . _:b566103598 . _:b566103599 . _:b566103588 . _:b566103592 . _:b566103618 "2"^^ . _:b566103593 . _:b566103594 . _:b566103595 . _:b566103636 . . _:b566103629 "2"^^ . _:b566103637 . _:b566103638 . _:b566103639 . _:b566103632 . _:b36135694 . _:b566103633 . _:b566103628 "2"^^ . _:b566103634 . . _:b36135726 "In both cases DAF-16 confers general stress resistance as observed upon starvation, heat, reactive oxygen species, and UV12,14,16,40,>>41<< likely through the induction of DBE-controlled genes." . _:b566103635 . _:b566103644 . _:b566103645 . _:b566103631 "2"^^ . _:b566103646 . _:b566103647 . . . _:b566103640 . _:b566103641 . _:b566103630 "2"^^ . _:b566103642 . _:b36135719 "In accordance with our observations, reduced IIS has been observed in progeroid mice lacking Sirtuin 636, or the NER factors Ercc1 or Csb and Xpa37,>>38<<. We previously showed that persistent DNA damage that leads to RNAPII stalling, the culprit of TC-NER deficiencies, evokes IIS attenuation in mammalian cells39." . . _:b566103643 . . _:b566103620 . _:b566103621 . _:b566103625 "2"^^ . . _:b566103622 . _:b566103579 . _:b566103623 . _:b566103616 . . _:b566103617 . _:b566103624 "2"^^ .