Details

Autor(en) / Beteiligte

• Liang, Fenfei
• Jin, Jiaxing
• Li, Qiming
• Duan, Jiangkai
• Jiang, Ao
• Chen, Xiaoqing
• Geng, Huichao
• Wu, Kai
• Yu, Fei
• Zhao, Xiaolu
• Zhou, Yu
• Hu, Deqing
• Chen, Liang

Titel

DOT1L/H3K79me2 represses HIV-1 reactivation via recruiting DCAF1

Ist Teil von

• Cell reports (Cambridge), 2024-07, Vol.43 (7), p.114368, Article 114368

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2024

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• DOT1L mediates the methylation of histone H3 at lysine 79 and, in turn, the transcriptional activation or repression in a context-dependent manner, yet the regulatory mechanisms and functions of DOT1L/H3K79me remain to be fully explored. Following peptide affinity purification and proteomic analysis, we identified that DCAF1—a component of the E3 ligase complex involved in HIV regulation—is associated with H3K79me2 and DOT1L. Interestingly, blocking the expression or catalytic activity of DOT1L or repressing the expression of DCAF1 significantly enhances the tumor necrosis factor alpha (TNF-α)/nuclear factor κB (NF-κB)-induced reactivation of the latent HIV-1 genome. Mechanistically, upon TNF-α/NF-κB activation, DCAF1 is recruited to the HIV-1 long terminal repeat (LTR) by DOT1L and H3K79me2. Recruited DCAF1 subsequently induces the ubiquitination of NF-κB and restricts its accumulation at the HIV-1 LTR. Altogether, our findings reveal a feedback modulation of HIV reactivation by DOT1L-mediated histone modification regulation and highlight the potential of targeting the DOT1L/DCAF1 axis as a therapeutic strategy for HIV treatment. [Display omitted] •Peptide affinity purification identifies proteins recognizing methylated histone H3K79•DCAF1 is associated with both H3K79me2 and DOT1L•DOT1L/H3K79me2 facilitates recruitment of DCAF1 to constrain HIV-1 reactivation•DCAF1 promotes ubiquitination of NF-κB and suppresses its level at HIV-1 LTR Liang et al. demonstrated that DOT1L/H3K79me2, in conjunction with DCAF1, establishes a negative feedback loop to restrict HIV-1 reactivation by inhibiting NF-κB binding at LTR.