Multifaceted role of TREX2 in the skin defense against UV-induced skin carcinogenesis

Abstract

TREX2 is a 3′-DNA exonuclease specifically expressed in keratinocytes. Here, we investigated the relevance and mechanisms of TREX2 in ultraviolet (UV)-induced skin carcinogenesis. TREX2 expression was up-regulated by chronic UV exposure whereas it was de-regulated or lost in human squamous cell carcinomas (SCCs). Moreover, we identified SNPs in the TREX2 gene that were more frequent in patients with head and neck SCCs than in healthy individuals. In mice, TREX2 deficiency led to enhanced susceptibility to UVB-induced skin carcinogenesis which was preceded by aberrant DNA damage removal and degradation as well as reduced inflammation. Specifically, TREX2 loss diminished the up-regulation of IL12 and IFNγ, key cytokines related to DNA repair and antitumor immunity. In UV-treated keratinocytes, TREX2 promoted DNA repair and passage to late apoptotic stages. Notably, TREX2 was recruited to low-density nuclear chromatin and micronuclei, where it interacted with phosphorylated H2AX histone, which is a critical player in both DNA repair and cell death. Altogether, our data provide new insights in the molecular mechanisms of TREX2 activity and establish cell autonomous and non-cell autonomous functions of TREX2 in the UVB-induced skin response.

The Exonuclease Trex2 Shapes Psoriatic Phenotype

“…This is in agreement with previous data demonstrating that TREX2 interacts with phosphorylated histone H2AX (γH2AX) (Manils et al, 2015), a critical player in both DNA repair and DNA degradation (Baritaud et al, 2010;Lu et al, 2006). Additionally, it has been shown that TREX2 can modulate DNA double-strand break repair (Bennardo et al, 2009) and replication fork stalling following DNA damage (Hu et al, 2013).…”

“…Deficiencies in these nucleases lead to the accumulation of self DNA, which triggers a strong type I interferon signature and results in autoinflammatory diseases (Gall et al, 2012;Grieves et al, 2015;Yoshida et al, 2005). In contrast, TREX2 deficiency dampened the inflammatory response in a IMQ-induced psoriasis-like mouse model, and in response to ultraviolet-B radiation (Manils et al, 2015). These data support a non-redundant positive regulatory role for this exonuclease in skin inflammatory responses under stress conditions.…”

“…Interestingly, neither spontaneous tumors nor chromosomal instability have been observed in Trex2 -/-mice (Parra et al, 2009). However, TREX2 deficiency in mice leads to increased susceptibility to carcinogeninduced skin tumorigenesis (Manils et al, 2015;Parra et al, 2009), indicating a critical role for this exonuclease in the skin homeostasis upon DNA damage. Here, we demonstrate that TREX2 further contributes to the pathogenesis of psoriasis by promoting DNA degradation, keratinocyte death and skin inflammation.…”

TREX through Cutaneous Health and Disease

“…However, TREX2knockout mice are more susceptible to skin carcinogenesis induced by UVB radiation exposure or application of 7, 12-dimethylbenz[a]anthracene, a DNAdamaging carcinogen. These findings correlate with a decrease in keratinocyte apoptosis and a decrease in inflammatory responses induced after DNA damage in TREX2-deficient mice (Manils et al, 2015;Parra et al, 2009). These studies indicate that TREX2 can degrade damaged nucleic DNA, leading to keratinocyte cell death and activation of an inflammatory immune response that normally clears damaged cells and prevents the development of cutaneous tumors.…”

“…Knowing that TREX2 mRNA is upregulated significantly in psoriatic lesions (Li et al, 2014) and that TREX2 can lead to the induction of mediators of innate inflammatory responses, such as tumor necrosis factor-a, inducible nitric oxide synthase, IL-6, and IFN-g (Manils et al, 2015), Manils et al (2016) examined the role of TREX2 in the pathogenesis of psoriasis. Their studies found that loss of TREX2 abrogated the inflammation that is normally induced in two acute murine models of psoriasis, the imiquimod and recombinant IL-23 models.…”