Aicardi-Goutières syndrome-associated gene SAMHD1 preserves genome integrity by preventing R-loop formation at transcription–replication conflict regions
Autoři:
Kiwon Park aff001; Jeongmin Ryoo aff003; Heena Jeong aff001; Minsu Kim aff001; Sungwon Lee aff001; Sung-Yeon Hwang aff001; Jiyoung Ahn aff004; Doyeon Kim aff002; Hyungseok C. Moon aff005; Daehyun Baek aff002; Kwangsoo Kim aff006; Hye Yoon Park aff005; Kwangseog Ahn aff001
Působiště autorů:
Center for RNA Research, Institute for Basic Science, Seoul, Republic of Korea
aff001; School of Biological Sciences, Seoul National University, Seoul, Republic of Korea
aff002; Department of Hematology, Oncology and Stem Cell transplantation, Comprehensive Cancer center Freiburg, University of Freiburg, Freiburg, Germany
aff003; Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
aff004; Department of Physics and Astronomy, Seoul National University, Seoul, Republic of Korea
aff005; Transdisciplinary Department of Medicine & Advanced Technology, Seoul National University Hospital, Seoul, Republic of Korea
aff006
Vyšlo v časopise:
Aicardi-Goutières syndrome-associated gene SAMHD1 preserves genome integrity by preventing R-loop formation at transcription–replication conflict regions. PLoS Genet 17(4): e1009523. doi:10.1371/journal.pgen.1009523
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1009523
Souhrn
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.
Klíčová slova:
Colorectal cancer – Cancer genomics – DNA damage – DNA replication – Fibroblasts – Genomics – Lung and intrathoracic tumors – Synthesis phase
Zdroje
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