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−/−Smg1gt/+ 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−/−Smg1gt/+ 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.

Non‐coding RNA‐associated competitive endogenous RNA regulatory networks: Novel diagnostic and therapeutic opportunities for hepatocellular carcinoma

“…Suppressor with morphogenetic effect on genitalia ( SMG1 ) is a member of phosphatidylinositol 3‐kinase‐related protein kinases ( PIKK s). 161 , 162 SMG1 has a well‐known role in nonsense‐mediated decay ( NMD ), which is responsible for the degradation of mRNAs containing premature termination codons and has also been reported to be implicated in the regulation of DNA damage responses, oxidative and hypoxic stress responses, telomere maintenance and stress granule formation. SMG1 has been found to suppress tumour growth by regulation of both p53 and Cdc25A signalling pathways.…”

Mitochondria-Targeted Antioxidants: A Step towards Disease Treatment

“…The present review article is aimed at summarizing experimental data on mitochondria-targeted antioxidants (MTAs) for various disease treatments in different models and clinical trials to present the evidence supporting the therapeutic potential of these MTAs. We specifically focused on brain neurological diseases [ 10 , 11 ], cardiovascular diseases [ 12 – 14 ], and cancer development [ 15 , 16 ], all of which are closely associated with oxidative damage and signal activation caused by the excess accumulation of ROS in mitochondria. Meanwhile, the potential MTA applications in disease treatment, their limitations, and prospects for exploiting MTAs are discussed.…”

Circular RNA CircPPP1CB Suppresses Tumorigenesis by Interacting With the MiR-1307-3p/SMG1 Axis in Human Bladder Cancer

“…SMG1 was involved in nonsense-mediated mRNA decay and was a member of PI3-kinase-like-related kinase family exerting vital roles in cellular stress and DNA damage responses ( Yamashita et al, 2001 ; McIlwain et al, 2010 ; Chen et al, 2017 ; Ho et al, 2019 ). Loss of SMG1 completely leads to early embryonic lethal, but mice with SMG1 haploinsufficiency represent a predisposition to chronic inflammation, oxidative stress, and tumorigenesis ( Roberts et al, 2013 ).…”