Radiation-induced DNA damage and repair effects on 3D genome organization

DNA Double-Strand Break (DSB) repair is essential to safeguard genome integrity. Upon DSBs, the ATM PI3K kinase rapidly triggers the establishment of megabase-sized, γH2AX-decorated chromatin domains which further act as seeds for the formation of DNA Damage Response (DDR) foci 1 . How these foci are rapidly assembled in order to establish a “repair-prone” environment within the nucleus is yet unclear. Topologically Associating Domains (TADs) are a key feature of 3D genome organization that compartmentalize transcription and replication, but little is known about their contribution to DNA repair processes 2 , 3 . Here we found that TADs are functional units of the DDR, instrumental for the correct establishment of γH2AX/53BP1 chromatin domains in a manner that involves one-sided cohesin-mediated loop extrusion on both sides of the DSB. We propose a model whereby H2AX-containing nucleosomes are rapidly phosphorylated as they actively pass by DSB-anchored cohesin. Our work highlights the critical impact of chromosome conformation in the maintenance of genome integrity and provides the first example of a chromatin modification established by loop extrusion.

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“…A Western Blot was used to verify the degradation of Pds5::9myc-AID in yFZ014 and yFZ016 after auxin addition. DSB were induced as in 33 .…”

Section: Methodsmentioning

confidence: 99%

“…Previous work indicated a genome-wide increase of cohesin and reinforcement of TADs following exposure to irradiation 33 , 34 . In agreement, we found that SCC1 enrichment was increased at cohesin-binding sites post-break induction, coinciding with an increased loop strength ( Extended Data Fig.…”

Section: Cohesin Changes In Damaged Tadsmentioning

confidence: 97%

Loop extrusion as a mechanism for formation of DNA damage repair foci

Arnould

Rocher

Finoux

et al. 2021

Nature

193

215

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“…Unlike our findings with Su(Hw), CTCF depletion in MEFs increases H2AX phosphorylation but, similar to Su(Hw) depletion in flies, induces genome instability (Lang et al , 2017), possibly indicating a different mechanism linking CTCF to H2AX phosphorylation. The link between DNA damage repair and insulator proteins is further corroborated by the recent finding that TAD boundary strength and CTCF insulation strength both increase in an ATM-dependent manner in human cell culture after X-ray-induced DNA damage (Sanders et al , 2020).…”

Section: Discussionmentioning

confidence: 72%

A Phosphorylated Histone H2A Variant Displays Properties of Chromatin Insulator Proteins inDrosophila

Simmons

Amankwaa

et al. 2021

Preprint

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Chromatin insulators are responsible for mediating long-range interactions between enhancers and promoters throughout the genome and align with the boundaries of topologically associating domains (TADs). Here, we demonstrate an interaction between proteins that associate with the gypsy insulator and the phosphorylated histone variant H2Av (γH2Av), a marker of DNA double strand breaks. Gypsy insulator components colocalize with γH2Av throughout the genome. Mutation of insulator components prevents stable H2Av phosphorylation in polytene chromatin. Phosphatase inhibition strengthens the association between insulator components and γH2Av and rescues γH2Av localization in insulator mutants. We also show that γH2Av is a component of insulator bodies, and that phosphatase activity is required for insulator body dissolution after recovery from osmotic stress. We further demonstrate a tight association between γH2Av and TAD boundaries. Together, our results indicate a novel mechanism linking insulator function with a histone H2A variant and with genome stability.

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“…Among them, ATM , TP53 , and FOXO3 belonged to each cluster. ATM serves as a regulator of a variety of downstream proteins, including tumor suppressor proteins ( Sanders et al, 2020 ). FOXO3 may well induce apoptosis in melanoma cells by the expression of requisite genes ( Segura et al, 2009 ).…”

Section: Resultsmentioning

confidence: 99%

Single-Cell Transcriptome Analysis in Melanoma Using Network Embedding

Wang¹,

Liu²,

Du³

et al. 2021

Front. Genet.

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Single-cell sequencing technology provides insights into the pathology of complex diseases like cancer. Here, we proposed a novel computational framework to explore the molecular mechanisms of cancer called melanoma. We first constructed a disease-specific cell–cell interaction network after data preprocessing and dimensionality reduction. Second, the features of cells in the cell–cell interaction network were learned by node2vec which is a graph embedding technology proposed previously. Then, consensus clusters were identified by considering different clustering algorithms. Finally, cell markers and cancer-related genes were further analyzed by integrating gene regulation pairs. We exploited our model on two independent datasets, which showed interesting results that the differences between clusters obtained by consensus clustering based on network embedding (CCNE) were observed obviously through visualization. For the KEGG pathway analysis of clusters, we found that all clusters are extremely related to MicroRNAs in cancer and HTLV-I infection, and the hub genes in cluster specific regulatory networks, i.e., ETS1, TP53, E2F1, and GATA3 are highly associated with melanoma. Furthermore, our method can also be extended to other scRNA-seq data.

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Radiation-induced DNA damage and repair effects on 3D genome organization

Cited by 75 publications

References 70 publications

Loop extrusion as a mechanism for formation of DNA damage repair foci

Loop extrusion as a mechanism for formation of DNA damage repair foci

A Phosphorylated Histone H2A Variant Displays Properties of Chromatin Insulator Proteins inDrosophila

Single-Cell Transcriptome Analysis in Melanoma Using Network Embedding

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