Increased Susceptibility to Skin Carcinogenesis in TREX2 Knockout Mice

Abstract

TREX2 is a proofreading 3 ¶-5 ¶ exonuclease that can be involved in genome maintenance; however, its biological role remains undefined. To better understand the function and physiologic relevance of TREX2, we generated mice deficient in TREX2 by targeted disruption of its unique coding exon. The knockout mice are viable and do not show relevant differences in growth, survival, lymphocyte development, or spontaneous tumor incidence compared with their wild-type counterparts over a period of up to 2 years. Also, we did not observe chromosomal instability or defects in cell proliferation and cell cycle upon loss of TREX2. We have observed that TREX2 expression is not ubiquitous, being expressed preferentially in tissues with stratified squamous epithelia, such as the skin or esophagus, and specifically in keratinocytes. Interestingly, TREX2-null mice are more susceptible to skin carcinogenesis induced by 7,12-dimethylbenz(a)anthracene (DMBA) compared with wild-type mice. This phenotype correlates with a reduction of DMBA-induced apoptosis in both the epidermis and keratinocytes of TREX2-null mice. Altogether, our results suggest a tumor suppressor role for TREX2 in skin carcinogenesis through which it contributes to keratinocyte apoptosis under conditions of genotoxic stress. [Cancer Res 2009;69(16):6676-84]

The TREX1 Exonuclease R114H Mutation in Aicardi-Goutières Syndrome and Lupus Reveals Dimeric Structure Requirements for DNA Degradation Activity

“…TREX1 and TREX2 have similar homodimeric structures with distinct elements that point to different biological roles (19,20). Deletion of the TREX2 gene in mice increases susceptibility to induced skin carcinogenesis (21), contrasting the autoimmune phenotype of the TREX1 knock-out mouse. The TREX1 dimer has an 8-amino acid polyproline II helix on the top and bottom of the front face and the TREX2 dimer has a ␤-hairpin in the same position.…”

“…5A, lanes [21][22][23][24][25][26] exhibit no detectable dsDNA degradation activity. However, the TREX1 R114H/D201ins (Fig.…”

The Exonuclease Trex2 Shapes Psoriatic Phenotype

“…Interestingly, the DNA exonuclease TREX2 is one of the genes that is most highly enriched in psoriatic lesions compared to normal skin (Li et al, 2014). Furthermore, TREX2 expression is restricted to keratinocytes, where it contributes to approximately half of the 3'-exonuclease activity of the epidermis (Parra et al, 2009).…”

“…Studies in heterologous cellular systems have shown that TREX2 may condition several DNA repair mechanisms (Aubert et al, 2014;Bennardo et al, 2009;Hu et al, 2013). 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.…”

079 Inactivation of DNase1L2 and DNase2 in keratinocytes suppresses DNA degradation during epidermal cornification and results in constitutive parakeratosis

“…We could exclude that this degradation depends on DNase1, which is also expressed in differentiating keratinocytes 23 . Other candidate contributors to cornification-associated DNA fragmentation include, but are not limited to, caspase-activated DNase (CAD), also known as DNA fragmentation factor B 24 and the exonuclease TREX2 10,25,26 . Like in suppression of DNA breakdown during programmed cell death of hair and nail keratinocytes 14 and sebocytes 15 , the blockade of DNA degradation by deletion of DNase1L2 and DNase2 prevented the complete removal of histone H3, a component of nucleosomes, whereas the inter-nucleosomal histone H1 and a nuclear protein without DNA interaction, lamin A/C, were degraded.…”