FANCD2 maintains replication fork stability during misincorporation of the DNA demethylation products 5-hydroxymethyl-2'-deoxycytidine and 5-hydroxymethyl-2'-deoxyuridine.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
27 05 2022
27 05 2022
Historique:
received:
25
10
2021
accepted:
13
05
2022
revised:
12
05
2022
entrez:
27
5
2022
pubmed:
28
5
2022
medline:
1
6
2022
Statut:
epublish
Résumé
Fanconi anemia (FA) is a rare hereditary disorder caused by mutations in any one of the FANC genes. FA cells are mainly characterized by extreme hypersensitivity to interstrand crosslink (ICL) agents. Additionally, the FA proteins play a crucial role in concert with homologous recombination (HR) factors to protect stalled replication forks. Here, we report that the 5-methyl-2'-deoxycytidine (5mdC) demethylation (pathway) intermediate 5-hydroxymethyl-2'-deoxycytidine (5hmdC) and its deamination product 5-hydroxymethyl-2'-deoxyuridine (5hmdU) elicit a DNA damage response, chromosome aberrations, replication fork impairment and cell viability loss in the absence of FANCD2. Interestingly, replication fork instability by 5hmdC or 5hmdU was associated to the presence of Poly(ADP-ribose) polymerase 1 (PARP1) on chromatin, being both phenotypes exacerbated by olaparib treatment. Remarkably, Parp1
Identifiants
pubmed: 35624090
doi: 10.1038/s41419-022-04952-0
pii: 10.1038/s41419-022-04952-0
pmc: PMC9142498
doi:
Substances chimiques
5-hydroxymethyl-2'-deoxycytidine
0
FANCD2 protein, human
0
Fanconi Anemia Complementation Group D2 Protein
0
Deoxycytidine
0W860991D6
5-hydroxymethyl-2'-deoxyuridine
5116-24-5
Thymidine
VC2W18DGKR
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
503Informations de copyright
© 2022. The Author(s).
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