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SMG1 heterozygosity exacerbates haematopoietic cancer development in Atm null mice by increasing persistent DNA damage and oxidative stress.

ABSTRACT: Suppressor of morphogenesis in genitalia 1 (SMG1) and ataxia telangiectasia mutated (ATM) are members of the PI3-kinase like-kinase (PIKK) family of proteins. ATM is a well-established tumour suppressor. Loss of one or both alleles of ATM results in an increased risk of cancer development, particularly haematopoietic cancer and breast cancer in both humans and mouse models. In mice, total loss of SMG1 is embryonic lethal and loss of a single allele results in an increased rate of cancer development, particularly haematopoietic cancers and lung cancer. In this study, we generated mice deficient in Atm and lacking one allele of Smg1, Atm^-/- Smg1^gt/+ mice. These mice developed cancers more rapidly than either of the parental genotypes, and all cancers were haematopoietic in origin. The combined loss of Smg1 and Atm resulted in a higher level of basal DNA damage and oxidative stress in tissues than loss of either gene alone. Furthermore, Atm^-/- Smg1^gt/+ mice displayed increased cytokine levels in haematopoietic tissues compared with wild-type animals indicating the development of low-level inflammation and a pro-tumour microenvironment. Overall, our data demonstrated that combined loss of Atm expression and decreased Smg1 expression increases haematopoietic cancer development.

SUBMITTER: Ho U

PROVIDER: S-EPMC6850945 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:All cellular processes, including those involved in normal cell metabolism to those responsible for cell proliferation or death, are finely controlled by cell signaling pathways, whose core proteins constitute the family of phosphatidylinositol 3-kinase-related kinases (PIKKs). Ataxia Telangiectasia Mutated (ATM) and Ataxia Telangiectasia and Rad3 related (ATR) are two important PIKK proteins that act in response to DNA damage, phosphorylating a large number of proteins to exert control over genomic integrity. The genus Leishmania belongs to a group of early divergent eukaryotes in evolution and has a highly plastic genome, probably owing to the existence of signaling pathways designed to maintain genomic integrity. The objective of this study was to evaluate the use of specific human inhibitors of ATR and ATM in Leishmania major. Bioinformatic analyses revealed the existence of the putative PIKK genes ATR and ATM, in addition to mTOR and DNA-PKcs in Leishmania spp. Moreover, it was possible to suggest that the inhibitors VE-821 and KU-55933 have binding affinity for the catalytic sites of putative L. major ATR and ATM, respectively. Promastigotes of L. major exposed to these inhibitors show slight growth impairment and minor changes in cell cycle and morphology. It is noteworthy that treatment of promastigotes with inhibitors VE-821 and KU-55933 enhanced the oxidative damage caused by hydrogen peroxide. These inhibitors could significantly reduce the number of surviving L. major cells following H2O2 exposure whilst also decreasing their evaluated IC50 to H2O2 to less than half of that observed for non-treated cells. These results suggest that the use of specific inhibitors of ATR and ATM in Leishmania interferes in the signaling pathways of this parasite, which can impair its tolerance to DNA damage and affect its genome integrity. ATR and ATM could constitute novel targets for drug development and/or repositioning for treatment of leishmaniases.

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SMG1 heterozygosity exacerbates haematopoietic cancer development in Atm null mice by increasing persistent DNA damage and oxidative stress.

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