In:
PLOS Genetics, Public Library of Science (PLoS), Vol. 17, No. 4 ( 2021-4-15), p. e1009523-
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.
Type of Medium:
Online Resource
ISSN:
1553-7404
DOI:
10.1371/journal.pgen.1009523
DOI:
10.1371/journal.pgen.1009523.g001
DOI:
10.1371/journal.pgen.1009523.g002
DOI:
10.1371/journal.pgen.1009523.g003
DOI:
10.1371/journal.pgen.1009523.g004
DOI:
10.1371/journal.pgen.1009523.g005
DOI:
10.1371/journal.pgen.1009523.s001
DOI:
10.1371/journal.pgen.1009523.s002
DOI:
10.1371/journal.pgen.1009523.s003
DOI:
10.1371/journal.pgen.1009523.s004
DOI:
10.1371/journal.pgen.1009523.s005
DOI:
10.1371/journal.pgen.1009523.s006
DOI:
10.1371/journal.pgen.1009523.s007
DOI:
10.1371/journal.pgen.1009523.s008
DOI:
10.1371/journal.pgen.1009523.s009
DOI:
10.1371/journal.pgen.1009523.s010
DOI:
10.1371/journal.pgen.1009523.r001
DOI:
10.1371/journal.pgen.1009523.r002
DOI:
10.1371/journal.pgen.1009523.r003
DOI:
10.1371/journal.pgen.1009523.r004
DOI:
10.1371/journal.pgen.1009523.r005
DOI:
10.1371/journal.pgen.1009523.r006
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2186725-2
Permalink