SETD1A function in leukemia is mediated through interaction with mitotic regulators BuGZ/BUB3.
BuGZ
DNA repair
Leukemia
SETD1A
Transcription
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
09 10 2023
09 10 2023
Historique:
revised:
11
07
2023
received:
02
03
2023
accepted:
18
07
2023
pmc-release:
03
08
2024
medline:
10
10
2023
pubmed:
3
8
2023
entrez:
3
8
2023
Statut:
ppublish
Résumé
The H3K4 methyltransferase SETD1A plays a crucial role in leukemia cell survival through its noncatalytic FLOS domain-mediated recruitment of cyclin K and regulation of DNA damage response genes. In this study, we identify a functional nuclear localization signal in and interaction partners of the FLOS domain. Our screen for FLOS domain-binding partners reveals that the SETD1A FLOS domain binds mitosis-associated proteins BuGZ/BUB3. Inhibition of both cyclin K and BuGZ/BUB3-binding motifs in SETD1A shows synergistic antileukemic effects. BuGZ/BUB3 localize to SETD1A-bound promoter-TSS regions and SETD1A-negative H3K4me1-positive enhancer regions adjacent to SETD1A target genes. The GLEBS motif and intrinsically disordered region of BuGZ are required for both SETD1A-binding and leukemia cell proliferation. Cell-cycle-specific SETD1A restoration assays indicate that SETD1A expression at the G1/S phase of the cell cycle promotes both the expression of DNA damage response genes and cell cycle progression in leukemia cells.
Identifiants
pubmed: 37535603
doi: 10.15252/embr.202357108
pmc: PMC10561176
doi:
Substances chimiques
Cyclins
0
Cell Cycle Proteins
0
BUB3 protein, human
0
Poly-ADP-Ribose Binding Proteins
0
Banques de données
GEO
['GSE159146', 'GSE189894']
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
e57108Subventions
Organisme : NCI NIH HHS
ID : R01 CA204396
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Informations de copyright
© 2023 The Authors.
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