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A HDAC4-HDAC2 complex composes an epigenetic sensor that links the DNA damage response to the senescent program by erasing H2BK120 acetylation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE216862 | GEO | 2024/06/18

REPOSITORIES: GEO

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A HDAC4-HDAC2 complex composes an epigenetic sensor that links the DNA damage response to the senescent program by erasing H2BK120 acetylation [I]

Project description:Purpose: Recognize the specific H2BK120ac profile around HDAC4 binding sites in proliferating, pre-senescent, senescent and senescence escaped cells during the accumulation of dsDNA damage, compared to undamaged regions. Outcome: We discovered a novel epigenetic complex formed by HDAC4 and HDAC2 that is involved in monitoring H2BK120 acetylation. The HDAC4/HDAC2 complex, through the dynamic deacetylation of H2BK120, modulates the efficiency of DNA repair by homologous recombination (HR) by controlling the recruitment of BRCA1 and CtIP to the site of lesions. Degradation of HDAC4 during senescence has a dual effect. First, it contributes to super-enhancers activation by limiting HDAC3 activity, and second, it causes the accumulation of DNA damage.

2024-06-18 | GSE216677 | GEO

A HDAC4-HDAC2 complex composes an epigenetic sensor that links the DNA damage response to the senescent program by erasing H2BK120 acetylation [II]

Project description:Purpose: Identification of SEs in time course after HDAC4 depletion and correlation to the accumulation of DNA damage. Outcome: We discovered a novel epigenetic complex formed by HDAC4 and HDAC2 that is involved in the erasure of H2BK120 acetylation. The HDAC4/HDAC2 complex, through the dynamic deacetylation of H2BK120, modulates the efficiency of DNA repair by homologous recombination (HR) by controlling the recruitment of BRCA1 and CtIP to the site of lesions. Degradation of HDAC4 during senescence has a dual effect. First, it contributes to super-enhancers activation by limiting HDAC3 activity, and second, it causes the accumulation of damaged DNA.

2024-06-18 | GSE216861 | GEO

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

Project description: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.

| S-EPMC11317144 | biostudies-literature

A HDAC4-HDAC2 complex composes an epigenetic sensor that links the DNA damage response to the senescent program by erasing H2BK120 acetylation

Project description:A HDAC4-HDAC2 complex composes an epigenetic sensor that links the DNA damage response to the senescent program by erasing H2BK120 acetylation

| PRJNA895718 | ENA

A HDAC4-HDAC2 complex composes an epigenetic sensor that links the DNA damage response to the senescent program by erasing H2BK120 acetylation [I]

Project description:A HDAC4-HDAC2 complex composes an epigenetic sensor that links the DNA damage response to the senescent program by erasing H2BK120 acetylation [I]

| PRJNA894954 | ENA

A HDAC4-HDAC2 complex composes an epigenetic sensor that links the DNA damage response to the senescent program by erasing H2BK120 acetylation [II]

Project description:A HDAC4-HDAC2 complex composes an epigenetic sensor that links the DNA damage response to the senescent program by erasing H2BK120 acetylation [II]

| PRJNA895720 | ENA

UV-damaged DNA-binding protein in the TFTC complex links DNA damage recognition to nucleosome acetylation.

Project description:Initiation of transcription of protein-encoding genes by RNA polymerase II (Pol II) was thought to require transcription factor TFIID, a complex comprised of the TATA box-binding protein (TBP) and TBP-associated factors (TAF(II)s). In the presence of TBP-free TAF(II) complex (TFTC), initiation of Pol II transcription can occur in the absence of TFIID. TFTC containing the GCN5 acetyltransferase acetylates histone H3 in a nucleosomal context. We have identified a 130 kDa subunit of TFTC (SAP130) that shares homology with the large subunit of UV-damaged DNA-binding factor. TFTC preferentially binds UV-irradiated DNA, UV-damaged DNA inhibits TFTC-mediated Pol II transcription and TFTC is recruited in parallel with the nucleotide excision repair protein XP-A to UV-damaged DNA. TFTC preferentially acetylates histone H3 in nucleosomes assembled on UV-damaged DNA. In agreement with this, strong histone H3 acetylation occurs in intact cells after UV irradiation. These results suggest that the access of DNA repair machinery to lesions within chromatin may be facilitated by TFTC via covalent modification of chromatin. Thus, our experiments reveal a molecular link between DNA damage recognition and chromatin modification.

| S-EPMC150203 | biostudies-literature

MRE11 complex links RECQ5 helicase to sites of DNA damage.

Project description:RECQ5 DNA helicase suppresses homologous recombination (HR) possibly through disruption of RAD51 filaments. Here, we show that RECQ5 is constitutively associated with the MRE11-RAD50-NBS1 (MRN) complex, a primary sensor of DNA double-strand breaks (DSBs) that promotes DSB repair and regulates DNA damage signaling via activation of the ATM kinase. Experiments with purified proteins indicated that RECQ5 interacts with the MRN complex through both MRE11 and NBS1. Functional assays revealed that RECQ5 specifically inhibited the 3'-->5' exonuclease activity of MRE11, while MRN had no effect on the helicase activity of RECQ5. At the cellular level, we observed that the MRN complex was required for the recruitment of RECQ5 to sites of DNA damage. Accumulation of RECQ5 at DSBs was neither dependent on MDC1 that mediates binding of MRN to DSB-flanking chromatin nor on CtIP that acts in conjunction with MRN to promote resection of DSBs for repair by HR. Collectively, these data suggest that the MRN complex recruits RECQ5 to sites of DNA damage to regulate DNA repair.

| S-EPMC2677886 | biostudies-literature

A direct HDAC4-MAP kinase crosstalk activates muscle atrophy program.

Project description:Prolonged deficits in neural input activate pathological muscle remodeling, leading to atrophy. In denervated muscle, activation of the atrophy program requires HDAC4, a potent repressor of the master muscle transcription factor MEF2. However, the signaling mechanism that connects HDAC4, a protein deacetylase, to the atrophy machinery remains unknown. Here, we identify the AP1 transcription factor as a critical target of HDAC4 in neurogenic muscle atrophy. In denervated muscle, HDAC4 activates AP1-dependent transcription, whereas AP1 inactivation recapitulates HDAC4 deficiency and blunts the muscle atrophy program. We show that HDAC4 activates AP1 independently of its canonical transcriptional repressor activity. Surprisingly, HDAC4 stimulates AP1 activity by activating the MAP kinase cascade. We present evidence that HDAC4 binds and promotes the deacetylation and activation of a key MAP3 kinase, MEKK2. Our findings establish an HDAC4-MAPK-AP1 signaling axis essential for neurogenic muscle atrophy and uncover a direct crosstalk between acetylation- and phosphorylation-dependent signaling cascades.

| S-EPMC3398192 | biostudies-literature

Pseudo-DNA damage response in senescent cells.

Project description:Cellular senescence is currently viewed as a response to DNA damage. In this report, we showed that non-damaging agents such as sodium butyrate-induced p21 and ectopic expression of either p21 or p16 cause cellular senescence without detectable DNA breaks. Nevertheless, senescent cells displayed components of DNA damage response (DDR) such as gammaH2AX foci and uniform nuclear staining for p-ATM. Importantly, there was no accumulation of 53BP1 in gammaH2AX foci of senescent cells. Consistently, comet assay failed to detect DNA damage. Rapamycin, an inhibitor of mTO R, which was shown to suppress cellular senescence, decreased gammaH2AX foci formation. Thus, cellular senescence leads to activation of atypical DDR without detectable DNA damage. Pseudo-DDR may be a marker of general over-activation of senescent cells.

| S-EPMC4970747 | biostudies-literature

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