Nontranscriptional Function of FOXO1/DAF-16 Contributes to Translesion DNA Synthesis

Abstract

Forkhead box O (FOXO; DAF-16 in nematodes) transcription factors activate a program of genes that control stress resistance, metabolism, and life span. Given the adverse impact of the stochastic DNA damage on organismal development and aging, we examined the role of FOXO/DAF-16 in UV-induced DNA damage response. Knockdown of FOXO1 but not of FOXO3a increases sensitivity to UV irradiation when exposed during S phase, suggesting a contribution of FOXO1 to translesion DNA synthesis (TLS), a replicative bypass of UV-induced DNA lesions. Actually, FOXO1 depletion results in sustained activation of ATR-Chk1 signaling and a reduction of proliferating cell nuclear antigen (PCNA) monoubiquitination following UV irradiation. FOXO1 does not alter the expression of TLS-related genes, but it binds to replication protein A 1 (RPA1), which coats single-stranded DNA and acts as a scaffold for TLS. In Caenorhabditis elegans, daf-16-null mutants show UV-induced retardation in larval development and are rescued by overexpressing a DAF-16 mutant lacking the transactivation domain but not a mutant whose amino acid substitutions render it unable to interact with RPA1. Thus, our findings demonstrate that FOXO1/DAF-16 is a functional component in TLS independent of its transactivation activity.

FOXO activity adaptation safeguards the hematopoietic stem cell compartment in hyperglycemia

“…This could suggest nontranscriptional nuclear FOXO functions in this particular context. 36 We can also speculate that the observed loss of FOXO regulation is one component of a broader dysregulation of the stress response. Particularly, in vivo AKT inhibition experiments suggest that constitutive AKT activation, along with its downstream targets such as mTOR, could also contribute to the altered HSC functions and increased resistance to oxidative stress through a FOXO-independent mechanism.…”

FoxO1 transcriptional activities in VEGF expression and beyond: a key regulator in functional angiogenesis?

“…The fundamental role of FoxO1 is to regulate gene transcription. Under specific conditions, this transcription factor can serve either as an activator or as a suppressor of gene expression in addition to its non‐transcriptional functions .…”

Differential Dose- and Tissue-Dependent Effects of foxo on Aging, Metabolic and Proteostatic Pathways

“…Apart from FOXO predominant transcriptional activity, there have been few recent reports that underlie its non-transcriptional activity [ 40 ]. The less well-known non-transcriptional FOXO function(s) relate to the interaction of cytoplasmic FOXO with other sub-cellular modules, such as RPA1 (Replication Protein A1) and ATM, regulating DNA synthesis and DNA damage responses, respectively; or with TSC2 controlling the insulin signaling pathway through mTOR and ATG7 managing the rate of protein degradation through autophagy [ 42 , 43 , 44 , 45 , 46 ]. However, since FOXO also transcriptionally regulates several of the aforementioned cellular processes, it remains to be determined how relevant these non-transcriptional functions are compared to the transcriptional regulation; if they are related to isoform-specific functions, and whether they could be associated with FOXO’s gene dosage since FOXO protein levels impact on the transcription factor’s cellular location, thereby affecting upstream signaling, triggering, for example, complex feedback signaling cascades aiming to suppress FOXO overactivation [ 40 ].…”