Aicardi-Goutieres syndrome-associated gene SAMHD1 preserves genome integrity by preventing R-loop formation at transcription-replication conflict regions

Author summary Mutations in SAMHD1 cause Aicardi-Goutieres syndrome (AGS), a monogenic lupus-like autoimmune disease. Among AGS-associated genes, SAMHD1 is most frequently mutates in various types of tumors and malignancies, suggesting that it is biologically relevant to cancer development. Here, we show that SAMHD1 resolves R-loops induced by transcription-replication conflicts, thereby contributing to the maintenance of genome stability. Our findings provide insight into the molecular and mechanical understanding of the autoimmunity and cancer comorbidity, and suggest that SAMHD1 and R-loops are potential and reliable biomarkers in anti-cancer therapeutics. The comorbid association of autoimmune diseases with cancers has been a major obstacle to successful anti-cancer treatment. Cancer survival rate decreases significantly in patients with preexisting autoimmunity. However, to date, the molecular and cellular profiles of such comorbidities are poorly understood. We used Aicardi-Goutieres syndrome (AGS) as a model autoimmune disease and explored the underlying mechanisms of genome instability in AGS-associated-gene-deficient patient cells. We found that R-loops are highly enriched at transcription-replication conflict regions of the genome in fibroblast of patients bearing SAMHD1 mutation, which is the AGS-associated-gene mutation most frequently reported with tumor and malignancies. In SAMHD1-depleted cells, R-loops accumulated with the concomitant activation of DNA damage responses. Removal of R-loops in SAMHD1 deficiency reduced cellular responses to genome instability. Furthermore, downregulation of SAMHD1 expression is associated with various types of cancer and poor survival rate. Our findings suggest that SAMHD1 functions as a tumor suppressor by resolving R-loops, and thus, SAMHD1 and R-loop may be novel diagnostic markers and targets for patient stratification in anti-cancer therapy.