Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Mammalian PERIOD complex regulates repair of DSB in active chromatin through anchoring to the nuclear envelope

ABSTRACT: Repair of DNA Double Strand Breaks produced in transcriptionally active chromatin occurs through a mechanism, Transcription-Coupled DSB repair (TC-DSBR), that is yet poorly characterized. Here, using a screening approach scoring multiple outputs in human cells, we identified the PER complex, a key module ensuring circadian oscillations, as a novel TC-DSBR player, being enriched at DSB occurring in transcribed loci, as compared to DSB induced in un-transcribed loci. We further found that PER2 contributes to target TC-DSBs at the nuclear envelope (NE) and to foster Rad51- mediated repair. PER2 deficiency triggers decreased DSB anchoring to NE, resulting in an increase of DSB clustering, checkpoint activation and translocation frequency. In agreement, we found that the circadian clock also regulates DSB anchoring to the NE, checkpoint activation, and HR usage. Our study provides a direct link between the circadian clock and the response to DNA Damage, opening new therapeutic strategies for chemotherapies based on topoisomerase poisons that induce DSBs in active loci.

INSTRUMENT(S): NextSeq 500, NextSeq 2000

ORGANISM(S): Homo sapiens

SUBMITTER: Vincent ROCHER

PROVIDER: E-MTAB-12712 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The naked mole-rat (NMR; Heterocephalus glaber) has recently gained considerable attention in the scientific community for its unique potential to unveil novel insights in the fields of medicine, biochemistry, and evolution. NMRs exhibit unique adaptations that include protracted fertility, cancer resistance, eusociality, and anoxia. This suite of adaptations is not found in other rodent species, suggesting that interrogating conserved and accelerated regions in the NMR genome will find regions of the NMR genome fundamental to their unique adaptations. However, the current NMR genome assembly has limits that make studying structural variations, heterozygosity, and non-coding adaptations challenging. We present a complete diploid naked-mole rat genome assembly by integrating long-read and 10X-linked read genome sequencing of a male NMR and its parents, and Hi-C sequencing in the NMR hypothalamus (N=2). Reads were identified as maternal, paternal or ambiguous (TrioCanu). We then polished genomes with Flye, Racon and Medaka. Assemblies were then scaffolded using the following tools in order: Scaff10X, Salsa2, 3d-DNA, Minimap2-alignment between assemblies, and the Juicebox Assembly Tools. We then subjected the assemblies to another round of polishing, including short-read polishing with Freebayes. We assembled the NMR mitochondrial genome with mitoVGP. Y chromosome contigs were identified by aligning male and female 10X linked reads to the paternal genome and finding male-biased contigs not present in the maternal genome. Contigs were assembled with publicly available male NMR Fibroblast Hi-C-seq data (SRR820318). Both assemblies have their sex chromosome haplotypes merged so that both assemblies have a high-quality X and Y chromosome. Finally, assemblies were evaluated with Quast, BUSCO, and Merqury, which all reported the base-pair quality and contiguity of both assemblies as high-quality. The assembly will next be annotated by Ensembl using public RNA-seq data from multiple tissues (SRP061363). Together, this assembly will provide a high-quality resource to the NMR and comparative genomics communities.

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Mammalian PERIOD complex regulates repair of DSB in active chromatin through anchoring to the nuclear envelope

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