The chromatin remodeler RSF1 coordinates epigenetic marks for transcriptional repression and DSB repair

Abstract

DNA lesions impact on local transcription and the damage-induced transcriptional repression facilitates efficient DNA repair. However, how chromatin dynamics cooperates with these two events remained largely unknown. We here show that histone H2A acetylation at K118 is enriched in transcriptionally active regions. Under DNA damage, the RSF1 chromatin remodeling factor recruits HDAC1 to DSB sites. The RSF1-HDAC1 complex induces the deacetylation of H2A(X)-K118 and its deacetylation is indispensable for the ubiquitination of histone H2A at K119. Accordingly, the acetylation mimetic H2A-K118Q suppressed the H2A-K119ub level, perturbing the transcriptional repression at DNA lesions. Intriguingly, deacetylation of H2AX at K118 also licenses the propagation of γH2AX and recruitment of MDC1. Consequently, the H2AX-K118Q limits DNA repair. Together, the RSF1-HDAC1 complex controls the traffic of the DNA damage response and transcription simultaneously in transcriptionally active chromatins. The interplay between chromatin remodelers and histone modifiers highlights the importance of chromatin versatility in the maintenance of genome integrity.

The RPA–RNF20–SNF2H cascade promotes proper chromosome segregation and homologous recombination repair

“…However, its role in HR seems to depend on the chromatin relaxation activity of SNF2H rather than on RSF1 ( 41 , 49 ). In contrast to SNF2H, RSF1 appears to act by facilitating the deposition of centromere proteins CENP-S and CENP-X at DSBs or recruiting HDAC1 to promote transcriptional repression at DSBs ( 78 – 80 ). Thus, SNF2H and RSF1 exert different functions in DNA repair ( 40 , 41 , 43 , 49 , 79 ).…”

ARID1A regulates DNA repair through chromatin organization and its deficiency triggers DNA damage-mediated anti-tumor immune response

“…Since HR-prone DSBs are located close to promoters of actively transcribed genes and are more abundant in transcription-elongation associated histone marks, while NHEJ-prone DSBs are not ( 44 ); thus, transcription might be suppressed at HR-prone DSBs during DNA repair. We analyzed the accumulation of histone H2A acetylated at lysine 118 (H2K118ac), known to be enriched in transcriptionally active regions and to regulate transcription suppression during DSB repair ( 79 ). After DSB induction (T0), a reduced level of H2AK118ac was observed in WT but not in ARID1A-KO cells; the level recovered later at T4 (Figure 4C ).…”

“…ChIP-qPCR confirmed the enhanced enrichment of H2AK118ac in KO cells before DSB induction, showing further increase after DSB induction, whereas a decrease in the H2AK118ac level was detected after DSB induction in WT cells (Figure 4E ). The HDAC1 complex together with the chromatin remodeler RSF1 induces the de-acetylation of H2AK118ac; this de-acetylation precedes the ubiquitination of histone H2A at lysine 119, which in turn promotes the displacement of the elongating RNAPII and represses the transcription at adjacent TSS ( 79 ). ARID1A was reported to interact with HDAC1 and promote HDAC1 recruitment to chromatin ( 80 ).…”

Transcriptional regulation and chromatin dynamics at DNA double-strand breaks

“…The RSF1-HDAC1 complex deacetylates H2A-K118ac, which is enriched at sites of active transcription, to allow efficient ubiquitination of H2A at K119, in turn inducing transcriptional silencing. This temporal regulation of H2A-K118 deacetylation and H2A-K119 ubiquitination mediates crosstalk between transcription and the DDR, further promoting ɣH2AX propagation and DSB repair 73 . Preexisting histone modifications, such as H2AX-pY142 and H2A(X)-K118ac, in transcribed chromatin are regulated by ISWI family members to allow transcriptional repression in cis to DNA damage for efficient DNA repair by ɣH2AX propagation.…”

“…The subunits in the NuRD complex, such as HDAC1, normally repress transcription; thus, the recruitment of the NuRD complex may have pivotal roles in subsequent transcriptional silencing at transcribed loci 72 . Recently, ISWI chromatin remodeling complexes were found to be critical for DSB-induced transcriptional silencing 37 , 73 (Fig. 4 ).…”