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.
Highlights
TREX2 is a non-processive 3′–5′ exonuclease that may be involved in genome maintenance by editing 3′-ends in multiple pathways, ranging from DNA replication, recombination and repair to degradation
Immunofluorescence images reveal that TREX2 expression was mainly detected in the suprabasal layers of the epidermis, where keratinocytes became differentiated as evidenced by keratin 10 (K10) expression (Supplemental Fig. 1A)
These results demonstrated that TREX2 expression in keratinocytes was regulated during differentiation and by UVB radiation.The analysis of TREX2 by immunofluorescence in human precancerous actinic keratosis lesions and keratinocyte-derived tumors, including cutaneous squamous cell carcinomas (cSCCs) (Fig. 1C-1D) and head and neck SCCs (HNSCCs) (Table 1), revealed a frequent deregulated expression of this exonuclease in squamous carcinogenesis
Summary
TREX2 is a non-processive 3′–5′ exonuclease that may be involved in genome maintenance by editing 3′-ends in multiple pathways, ranging from DNA replication, recombination and repair to degradation. TREX2 ectopic co-expression with rare-cleaving endonucleases demonstrates that TREX2 can alter the normal function of end-joining DSB repair pathways. TREX2 processing of 3′-ends abrogates precise rejoining of endonuclease-induced breaks through the nonhomologous end joining (NHEJ) pathway that determines resolution of mutagenic breaks [7,8,9]. Recent work in a heterologous cellular context shows that TREX2 can be a component of the error-free post-replication repair (EF-PRR) system, which is required to bypass damage that blocks replicative DNA polymerases [10]. Upon DNA damage TREX2 can potentially participate in multiple pathways related to maintenance of genome stability. The physiological relevance of TREX2 in native cells remains elusive
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