Page 166 - ebook

[B. Cell Biology/Stem Cell] B-18

Aicardi-Goutières syndrome-associated gene SAMHD1

preserves genome integrity by preventing R-loop formation

at transcription–replication conflict regions

Kiwon Park¹, Doyeon Kim¹, Daehyun Baek¹, Jiyoung Ahn², Kwangsoo Kim³, Hye Yoon Park⁴,

Hyungseok C. Moon⁴, Kwangseog Ahn¹*

¹School of Biological Sciences , Seoul National University, Seoul 08826, Korea, ²Biomedical Research Institute,

Seoul National University Hospital, Seoul 03080, Korea, ³Transdisciplinary Department of Medicine & Advanced
Technology, Seoul National University Hospital, Seoul 03080, Korea, ⁴Department of Physics and Astronomy, Seoul

National University, Seoul 08826, Korea

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-Goutières
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.