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Non-canonical ATM/MRN activities temporally define the senescence secretory program.

ABSTRACT: Senescent cells display senescence-associated (SA) phenotypic programs such as stable proliferation arrest (SAPA) and a secretory phenotype (SASP). Senescence-inducing persistent DNA double-strand breaks (pDSBs) cause an immediate DNA damage response (DDR) and SAPA, but the SASP requires days to develop. Here, we show that following the immediate canonical DDR, a delayed chromatin accumulation of the ATM and MRN complexes coincides with the expression of SASP factors. Importantly, histone deacetylase inhibitors (HDACi) trigger SAPA and SASP in the absence of DNA damage. However, HDACi-induced SASP also requires ATM/MRN activities and causes their accumulation on chromatin, revealing a DNA damage-independent, non-canonical DDR activity that underlies SASP maturation. This non-canonical DDR is required for the recruitment of the transcription factor NF-κB on chromatin but not for its nuclear translocation. Non-canonical DDR further does not require ATM kinase activity, suggesting structural ATM functions. We propose that delayed chromatin recruitment of SASP modulators is the result of non-canonical DDR signaling that ensures SASP activation only in the context of senescence and not in response to transient DNA damage-induced proliferation arrest.

SUBMITTER: Malaquin N

PROVIDER: S-EPMC7534619 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Patterns and levels of DNA modifications play important roles in senescence. Two major epigenetic modifications of DNA, 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), target CpG sites. Importantly, CpG concentrated regions, known as CpG islands, contain GC-rich sequences, which have the potential to fold into non-canonical DNA structures such as i-motifs and G-quadruplexes. In this study, we investigated the effect of 5mC and 5hmC modifications on the transition between a duplex, and i-motif and G-quadruplexes. To examine the transition, we firstly investigated the stability and structure of the i-motif and G-quadruplexes, considering the molecular environment in senescent cells. Analyses of their stability showed that the modifications did not drastically affect the stability. However, noteworthily, the modification can weaken the (de)stabilisation effect on G-quadruplexes caused by cosolute(s) and cations. Circular dichroism analyses indicated that the surrounding environments, including the molecular crowding and the type of cations such as K+ and Na+, regulate the topology of G-quadruplexes, while neither 5mC nor 5hmC had a drastic effect. On the other hand, the modifications changed the transition between duplexes and quadruplexes. Unmodified DNA preferred to fold into quadruplexes, whereas DNA with 5mC and 5hmC preferred to fold into duplexes in the absence of PEG200; on the other hand, DNA with or without modifications tended to fold into i-motifs under crowded conditions. Furthermore, an investigation of quadruplexes forming sequences in CpG islands, which are hyper- or hypomethylated during senescence, followed by gene ontology enrichment analysis for each gene group classified by the presence of quadruplexes, showed a difference in function between genes with and without quadruplexes in the CpG region. These results indicate that it is important to consider the effects of patterns and levels of DNA modifications on the transition between canonical and non-canonical DNA structures to understand gene regulation by epigenetic modification during senescence.

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Non-canonical ATM/MRN activities temporally define the senescence secretory program.

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