HDAC4 influences the DNA damage response and counteracts senescence by assembling with HDAC1/HDAC2 to control H2BK120 acetylation and homology-directed repair.

Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE

Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.

DNA Damage* ; Histone Deacetylase 1*/metabolism ; Histone Deacetylase 1*/genetics ; Histone Deacetylase 2*/metabolism ; Histone Deacetylase 2*/genetics ; Histone Deacetylases*/metabolism ; Histone Deacetylases*/genetics ; Histones*/metabolism; Humans ; Acetylation ; BRCA1 Protein/metabolism ; BRCA1 Protein/genetics ; Cell Line ; Cellular Senescence ; Recombinational DNA Repair ; Repressor Proteins/metabolism ; Repressor Proteins/genetics

Access to DNA is the first level of control in regulating gene transcription, a control that is also critical for maintaining DNA integrity. Cellular senescence is characterized by profound transcriptional rearrangements and accumulation of DNA lesions. Here, we discovered an epigenetic complex between HDAC4 and HDAC1/HDAC2 that is involved in the erase of H2BK120 acetylation. The HDAC4/HDAC1/HDAC2 complex modulates the efficiency of DNA repair by homologous recombination, through dynamic deacetylation of H2BK120. Deficiency of HDAC4 leads to accumulation of H2BK120ac, impaired recruitment of BRCA1 and CtIP to the site of lesions, accumulation of damaged DNA and senescence. In senescent cells this complex is disassembled because of increased proteasomal degradation of HDAC4. Forced expression of HDAC4 during RAS-induced senescence reduces the genomic spread of γH2AX. It also affects H2BK120ac levels, which are increased in DNA-damaged regions that accumulate during RAS-induced senescence. In summary, degradation of HDAC4 during senescence causes the accumulation of damaged DNA and contributes to the activation of the transcriptional program controlled by super-enhancers that maintains senescence.
(© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

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AIRC; 2020-2025 MFAG; Associazione Italiana per la Ricerca sul Cancro

0 (BRCA1 Protein)
EC 3.5.1.98 (HDAC1 protein, human)
EC 3.5.1.98 (HDAC2 protein, human)
EC 3.5.1.98 (HDAC4 protein, human)
EC 3.5.1.98 (Histone Deacetylase 1)
EC 3.5.1.98 (Histone Deacetylase 2)
EC 3.5.1.98 (Histone Deacetylases)
0 (Histones)
0 (Repressor Proteins)

Date Created: 20240614 Date Completed: 20240811 Latest Revision: 20240822

20250114

PMC11317144

10.1093/nar/gkae501

38874468