A localized nucleolar DNA damage response facilitates recruitment of the homology-directed repair machinery independent of cell cycle stage
Marjolein van Sluis,Brian McStay +1 more
TLDR
It is suggested that HR can be templated in cis and suggest a role for chromosomal context in the maintenance of NOR genomic stability.Abstract:
DNA double-strand breaks (DSBs) are repaired by two main pathways: nonhomologous end-joining and homologous recombination (HR). Repair pathway choice is thought to be determined by cell cycle timing and chromatin context. Nucleoli, prominent nuclear subdomains and sites of ribosome biogenesis, form around nucleolar organizer regions (NORs) that contain rDNA arrays located on human acrocentric chromosome p-arms. Actively transcribed rDNA repeats are positioned within the interior of the nucleolus, whereas sequences proximal and distal to NORs are packaged as heterochromatin located at the nucleolar periphery. NORs provide an opportunity to investigate the DSB response at highly transcribed, repetitive, and essential loci. Targeted introduction of DSBs into rDNA, but not abutting sequences, results in ATM-dependent inhibition of their transcription by RNA polymerase I. This is coupled with movement of rDNA from the nucleolar interior to anchoring points at the periphery. Reorganization renders rDNA accessible to repair factors normally excluded from nucleoli. Importantly, DSBs within rDNA recruit the HR machinery throughout the cell cycle. Additionally, unscheduled DNA synthesis, consistent with HR at damaged NORs, can be observed in G1 cells. These results suggest that HR can be templated in cis and suggest a role for chromosomal context in the maintenance of NOR genomic stability.read more
Citations
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Ribosome biogenesis in cancer: new players and therapeutic avenues
TL;DR: The most recent findings that provide new insights into the molecular basis of ribosome biogenesis in cancer are highlighted and the perspective on how these observations present opportunities for the design of new targeted cancer treatments is offered.
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Nuclear F-actin and myosins drive relocalization of heterochromatic breaks.
Christopher P Caridi,Carla D'Agostino,Taehyun Ryu,Grzegorz Zapotoczny,Laetitia Delabaere,Xiao Li,Varandt Y. Khodaverdian,Nuno Amaral,Nuno Amaral,Emily Lin,Alesandra R. Rau,Irene Chiolo +11 more
TL;DR: De novo nuclear actin filaments and myosins are identified as effectors of chromatin dynamics for heterochromatin repair and stability in multicellular eukaryotes.
Journal ArticleDOI
Chromatin and nucleosome dynamics in DNA damage and repair.
TL;DR: An overview of the function of chromatin structure and its dynamic changes in response to genotoxic stress is presented, focusing on both subnuclear organization and the physical mobility of DNA.
Journal ArticleDOI
Temporal and Spatial Uncoupling of DNA Double Strand Break Repair Pathways within Mammalian Heterochromatin
Katerina Tsouroula,Audrey Furst,Mélanie Rogier,Vincent Heyer,Anne Maglott-Roth,Alexia Ferrand,Bernardo Reina-San-Martin,Evi Soutoglou +7 more
TL;DR: It is proposed that the spatial disconnection between end resection and RAD51 binding prevents the activation of mutagenic pathways and illegitimate recombination and suggests a model in which the commitment to specific DNA repair pathways regulates DSB position.
Journal ArticleDOI
Genome-wide mapping of long-range contacts unveils clustering of DNA double-strand breaks at damaged active genes
François Aymard,Marion Aguirrebengoa,Emmanuelle Guillou,Biola M. Javierre,Béatrix Bugler,Coline Arnould,Vincent Rocher,Jason S. Iacovoni,Anna Biernacka,Magdalena Skrzypczak,Krzysztof Ginalski,Maga Rowicka,Peter Fraser,Gaëlle Legube +13 more
TL;DR: Investigation of clustering of DNA double-strand breaks in mammalian cells reveals that, when damaged, active genes, compared with the rest of the genome, exhibit a distinctive behavior, remaining largely unrepaired and clustered in G1, and being repaired via homologous recombination in postreplicative cells.
References
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Le Cong,F. A. Ran,David Benjamin Turitz Cox,Shuailiang Lin,Robert P. J. Barretto,Naomi Habib,Patrick D. Hsu,Xuebing Wu,Wenyan Jiang,Luciano A. Marraffini,Feng Zhang +10 more
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Journal ArticleDOI
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Prashant Mali,Luhan Yang,Kevin M. Esvelt,John Aach,Marc Güell,James E. DiCarlo,Julie E. Norville,George M. Church,George M. Church +8 more
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Journal ArticleDOI
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