ABSTRACT: The RecQ helicase family plays a vital role in maintaining genome stability, including DNA replication, recombination, and DNA repair. In human cells, there are five RecQ helicases: RECQL1, Bloom syndrome (BLM), Werner syndrome (WRN), RECQL4, and RECQL5. Dysfunction or absence of RecQ proteins is associated with genetic disorders, tumorigenesis, premature aging, and neurodegeneration. The biological importance of RecQ helicases is well established; However, it is still unknown the potential outcomes after DNA damage, and there is no systematic study yet to compare the behavioral changes amongst various RecQ-deficient mice. In this study, we investigated the effects of IR treatment on three RecQ-deficient mouse models (Recql1, Wrn and Recql4). Here we provided evidence that RecQ dysfunction impaired social ability and induced depressive-like behavior in mice, with or without irradiation stress, while abnormal cognitive behaviors only existed in RecQ-deficient mice without IR treatment, suggesting RecQ proteins contribute to mood and cognition. Furthermore, transcripts and metabolomics analysis revealed significant alterations in the RecQ-deficient mice, especially after IR treatment. Particularly, pathways related to neuronal and microglia functions, DNA damage repair, cell cycle, and reactive oxygen response were downregulated in the RecQ4 and Wrn mice. In addition, increased DNA damage responses were found in RecQ-deficient mice. Notably, two genes, Aldolase Fructose-Bisphosphate B (Aldob) and NADPH Oxidase 4 (Nox4), were differentially expressed in RecQ-deficient mice. Our finding suggested that RecQ dysfunction contributes to social and depressive-like behaviors in mice, and that aldolase activity may be associated with these changes, representing it as a potential therapeutic intervention. To understand what Neuroinflammation-related gene expression changes are induced by γ-irradiation in the WT, RecQ1, WRN, RecQ4 deficient mice. They were exposed the whole body with γ-irradiation (IR, 6 Gy), thereafter prefrontal cortex tissues were collected from each mouse and subjected to RNA isolation.
