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Aicardi-Goutières syndrome-associated gene SAMHD1 preserves genome integrity by preventing R-loop formation at transcription-replication conflict regions.
- Source :
-
PLoS genetics [PLoS Genet] 2021 Apr 15; Vol. 17 (4), pp. e1009523. Date of Electronic Publication: 2021 Apr 15 (Print Publication: 2021). - Publication Year :
- 2021
-
Abstract
- 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.<br />Competing Interests: The authors have declared that no competing interests exist.
- Subjects :
- Autoimmune Diseases immunology
Autoimmune Diseases pathology
Autoimmune Diseases of the Nervous System immunology
Autoimmune Diseases of the Nervous System pathology
Cell Line, Tumor
DNA Damage genetics
DNA Replication genetics
Fibroblasts metabolism
Genome, Human genetics
Humans
Mutation genetics
Neoplasms genetics
Neoplasms therapy
Nervous System Malformations immunology
Nervous System Malformations pathology
R-Loop Structures genetics
SAM Domain and HD Domain-Containing Protein 1 ultrastructure
Transcription, Genetic genetics
Transfection
Autoimmune Diseases genetics
Autoimmune Diseases of the Nervous System genetics
Genomic Instability genetics
Nervous System Malformations genetics
SAM Domain and HD Domain-Containing Protein 1 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7404
- Volume :
- 17
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- PLoS genetics
- Publication Type :
- Academic Journal
- Accession number :
- 33857133
- Full Text :
- https://doi.org/10.1371/journal.pgen.1009523