Epigenome Maintenance in Response to DNA Damage

Dabin, Juliette; Fortuny, Anna; Polo, Sophie E.

doi:10.1016/j.molcel.2016.04.006

Cited by 133 publications

(115 citation statements)

References 198 publications

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“…Here, we discover that Gadd45a deletion significantly attenuates the DDR, improves the maintenance and function of ISCs in G3 Terc −/− mice, and consequently prolongs lifespan of G3 Terc −/− mice. Mechanistically, Gadd45a facilitates telomeric heterochromatin remodeling via BER‐mediated active DNA demethylation in sub‐telomeric regions of G3 Terc −/− cells, which generates a uncondensed chromatin structure to promote DDR signaling . Together, our study suggests that stem cell function improvement and lifespan extension could be achieved by altering the site‐specific epigenetic dynamics, such as DNA methylation at telomeres/sub‐telomeres.…”

Section: Introductionmentioning

confidence: 74%

Telomeric epigenetic response mediated by Gadd45a regulates stem cell aging and lifespan

Diao

Wang

et al. 2018

EMBO Reports

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Progressive attrition of telomeres triggers DNA damage response (DDR) and limits the regenerative capacity of adult stem cells during mammalian aging. Intriguingly, telomere integrity is not only determined by telomere length but also by the epigenetic status of telomeric/sub-telomeric regions. However, the functional interplay between DDR induced by telomere shortening and epigenetic modifications in aging remains unclear. Here, we show that deletion of Gadd45a improves the maintenance and function of intestinal stem cells (ISCs) and prolongs lifespan of telomerase-deficient mice (G3 ). Mechanistically, Gadd45a facilitates the generation of a permissive chromatin state for DDR signaling by inducing base excision repair-dependent demethylation of CpG islands specifically at sub-telomeric regions of short telomeres. Deletion of Gadd45a promotes chromatin compaction in sub-telomeric regions and attenuates DDR initiation at short telomeres of G3 ISCs. Treatment with a small molecule inhibitor of base excision repair reduces DDR and improves the maintenance and function of G3 ISCs. Taken together, our study proposes a therapeutic approach to enhance stem cell function and prolong lifespan by targeting epigenetic modifiers.

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Section: Introductionmentioning

confidence: 74%

Telomeric epigenetic response mediated by Gadd45a regulates stem cell aging and lifespan

Diao

Wang

et al. 2018

EMBO Reports

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“…16. response. 15 In this context, our recent study gives new insights into the coordinated maintenance of genome and epigenome integrity and leads to a revised version of the ARR model (Fig. 1), but also opens up several unresolved issues regarding the contribution of histone dynamics to epigenome maintenance.…”

Section: Resultsmentioning

confidence: 97%

“…How the pre-damage chromatin state could be preserved in this context was elusive. 15 We addressed this question in our recent study, by combining real-time tracking of parental histones with local induction of DNA damage by a UV-C laser. 16 This provided important novel insights into parental histone mobilization following DNA damage, an understanding of the underlying mechanisms and of the contribution of parental histones to chromatin repair.…”

Section: Introductionmentioning

confidence: 99%

Choreography of parental histones in damaged chromatin

Dabin

Polo

2017

Nucleus

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In the cell nucleus, DNA repair machineries operate on a chromatin substrate, whose integrity is key for preserving cell functions and identity. Yet, it is still unclear how the epigenetic information conveyed by chromatin is maintained during the DNA repair process. We recently characterized the dynamics of parental histones coupled to UV-C damage repair in human cells, providing insights into how the pre-damage chromatin state may be restored. Here, we summarize our main findings and discuss them in the context of epigenome maintenance following DNA damage. We further address the mechanistic aspects of repair-coupled histone dynamics and develop working hypotheses regarding their functional relevance in the cellular response to genotoxic stress.

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“…The histone chaperons promote new histone deposition (50) with DNA damage specific histone modifications (51). This could reshape the epigenetic landscape leading to modulation of gene expression thus reprogramming the macrophage and altering its identity in response to genotoxic stress (31,52).…”

Section: Particularly the Expression Of Cd206 And Pd-l1 Indicate Simimentioning

confidence: 99%

ATM-mediated DNA damage response in macrophages primes phagocytosis and immune checkpoint regulation

Bansal

Neuhaus

Izquierdo-Alvarez

et al. 2020

Preprint

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Genotoxin-based cancer therapies trigger a DNA damage response (DDR) to eliminate cancer cells but similarly exert profound alterations to the immune cell compartment. Macrophages in the tumor microenvironment are important and multifaceted components in actively sustaining tumor progression but also in clearance of tumor cells and play an important role in the outcome of chemotherapy. Here, we report that post neo-adjuvant chemotherapy macrophages in tumor samples display elevated expression of the immune checkpoint PD-L1. We determined that chemotherapy or direct application of DNA damage to macrophages in vitro triggers a specific M DDR polarization phenotype characterized by increased phagocytic activity, elevated PD-L1 expression, and induction of endotoxin tolerance. Phospho-proteomics analysis revealed epigenetic alterations and ATM-dependent induction of senescence in macrophages upon DNA damage. We propose that ATM-induced senescence and PD-L1 immune checkpoint induction mediate a specific M DDR macrophage polarization that might contribute to chemotherapy responses. Furthermore, our results clarify the functional role of tumor associated macrophages in the context of DNA damage and combination therapies including checkpoint inhibition. 3 1 Pharmacologic Agents. 2005; 36.Goss Tusher V, Tibshirani R, Chu G. Significance analysis of microarrays applied to the ionizing radiation response. 37.Hall BM, Balan V, Gleiberman AS, Strom E, Krasnov P, Virtuoso LP, et al. p16 (Ink4a) and senescence-associated

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Epigenome Maintenance in Response to DNA Damage

Cited by 133 publications

References 198 publications

Telomeric epigenetic response mediated by Gadd45a regulates stem cell aging and lifespan

Telomeric epigenetic response mediated by Gadd45a regulates stem cell aging and lifespan

Choreography of parental histones in damaged chromatin

ATM-mediated DNA damage response in macrophages primes phagocytosis and immune checkpoint regulation

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