NKAP acts with HDAC3 to prevent R-loop associated genome instability.
Cell Death Differ
; 30(7): 1811-1828, 2023 07.
Article
em En
| MEDLINE
| ID: mdl-37322264
ABSTRACT
Persistent R-loop accumulation can cause DNA damage and lead to genome instability, which contributes to various human diseases. Identification of molecules and signaling pathways in controlling R-loop homeostasis provide important clues about their physiological and pathological roles in cells. Here, we show that NKAP (NF-κB activating protein) is essential for preventing R-loop accumulation and maintaining genome integrity through forming a protein complex with HDAC3. NKAP depletion causes DNA damage and genome instability. Aberrant accumulation of R-loops is present in NKAP-deficient cells and leads to DNA damage and DNA replication fork progression defects. Moreover, NKAP depletion induced R-loops and DNA damage are dependent on transcription. Consistently, the NKAP interacting protein HDAC3 exhibits a similar role in suppressing R-loop associated DNA damage and replication stress. Further analysis uncovers that HDAC3 functions to stabilize NKAP protein, independent of its deacetylase activity. In addition, NKAP prevents R-loop formation by maintaining RNA polymerase II pausing. Importantly, R-loops induced by NKAP or HDAC3 depletion are processed into DNA double-strand breaks by XPF and XPG endonucleases. These findings indicate that both NKAP and HDAC3 are novel key regulators of R-loop homeostasis, and their dysregulation might drive tumorigenesis by causing R-loop associated genome instability.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Instabilidade Genômica
/
Estruturas R-Loop
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Cell Death Differ
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China