APOBEC3B regulates R-loops and promotes transcription-associated mutagenesis in cancer.
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
10 2023
10 2023
Historique:
received:
12
07
2020
accepted:
17
08
2023
medline:
11
10
2023
pubmed:
22
9
2023
entrez:
21
9
2023
Statut:
ppublish
Résumé
The single-stranded DNA cytosine-to-uracil deaminase APOBEC3B is an antiviral protein implicated in cancer. However, its substrates in cells are not fully delineated. Here APOBEC3B proteomics reveal interactions with a surprising number of R-loop factors. Biochemical experiments show APOBEC3B binding to R-loops in cells and in vitro. Genetic experiments demonstrate R-loop increases in cells lacking APOBEC3B and decreases in cells overexpressing APOBEC3B. Genome-wide analyses show major changes in the overall landscape of physiological and stimulus-induced R-loops with thousands of differentially altered regions, as well as binding of APOBEC3B to many of these sites. APOBEC3 mutagenesis impacts genes overexpressed in tumors and splice factor mutant tumors preferentially, and APOBEC3-attributed kataegis are enriched in RTCW motifs consistent with APOBEC3B deamination. Taken together with the fact that APOBEC3B binds single-stranded DNA and RNA and preferentially deaminates DNA, these results support a mechanism in which APOBEC3B regulates R-loops and contributes to R-loop mutagenesis in cancer.
Identifiants
pubmed: 37735199
doi: 10.1038/s41588-023-01504-w
pii: 10.1038/s41588-023-01504-w
pmc: PMC10562255
doi:
Substances chimiques
DNA, Single-Stranded
0
Cytidine Deaminase
EC 3.5.4.5
Minor Histocompatibility Antigens
0
APOBEC3B protein, human
EC 3.5.4.5
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1721-1734Subventions
Organisme : NIAID NIH HHS
ID : R37 AI064046
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA243306
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES030993
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009138
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA234228
Pays : United States
Organisme : Cancer Research UK
ID : CRUK DF-0119
Pays : United Kingdom
Organisme : NIEHS NIH HHS
ID : R01 ES032547
Pays : United States
Organisme : Howard Hughes Medical Institute
ID : 812337
Pays : United States
Organisme : Wellcome Trust
ID : 203141/Z/16/Z
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R01 CA198279
Pays : United States
Organisme : Wellcome Trust
ID : WT210641/Z/18/Z
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : K99 AI147811
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA252081
Pays : United States
Informations de copyright
© 2023. The Author(s).
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