scholarly journals The NuRD chromatin–remodeling complex regulates signaling and repair of DNA damage

2010 ◽  
Vol 190 (5) ◽  
pp. 741-749 ◽  
Author(s):  
Godelieve Smeenk ◽  
Wouter W. Wiegant ◽  
Hans Vrolijk ◽  
Aldo P. Solari ◽  
Albert Pastink ◽  
...  
Keyword(s):  
Dna Damage ◽  
Chromatin Remodeling ◽  
Cell Cycle Progression ◽  
Histone Deacetylation ◽  
Dna Double Strand Breaks ◽  
Nucleosome Remodeling ◽  
Chromatin Remodeling Complex ◽  
Genome Wide ◽  
A Genome ◽  
A Subunit

Cells respond to ionizing radiation (IR)–induced DNA double-strand breaks (DSBs) by orchestrating events that coordinate cell cycle progression and DNA repair. How cells signal and repair DSBs is not yet fully understood. A genome-wide RNA interference screen in Caenorhabditis elegans identified egr-1 as a factor that protects worm cells against IR. The human homologue of egr-1, MTA2 (metastasis-associated protein 2), is a subunit of the nucleosome-remodeling and histone deacetylation (NuRD) chromatin-remodeling complex. We show that knockdown of MTA2 and CHD4 (chromodomain helicase DNA-binding protein 4), the catalytic subunit (adenosine triphosphatase [ATPase]) of NuRD, leads to accumulation of spontaneous DNA damage and increased IR sensitivity. MTA2 and CHD4 accumulate in DSB-containing chromatin tracks generated by laser microirradiation. Directly at DSBs, CHD4 stimulates RNF8/RNF168-dependent formation of ubiquitin conjugates to facilitate the accrual of RNF168 and BRCA1. Finally, we show that CHD4 promotes DSB repair and checkpoint activation in response to IR. Thus, the NuRD chromatin–remodeling complex is a novel regulator of DNA damage responses that orchestrates proper signaling and repair of DSBs.

scholarly journals The chromatin-remodeling factor CHD4 coordinates signaling and repair after DNA damage

2010 ◽  
Vol 190 (5) ◽  
pp. 731-740 ◽  
Author(s):  
Dorthe Helena Larsen ◽  
Catherine Poinsignon ◽  
Thorkell Gudjonsson ◽  
Christoffel Dinant ◽  
Mark R. Payne ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Chromatin Remodeling ◽  
Cell Cycle Progression ◽  
Clonogenic Survival ◽  
Dna Double Strand Breaks ◽  
Checkpoint Signaling ◽  
Strand Breaks ◽  
Delay Cell

In response to ionizing radiation (IR), cells delay cell cycle progression and activate DNA repair. Both processes are vital for genome integrity, but the mechanisms involved in their coordination are not fully understood. In a mass spectrometry screen, we identified the adenosine triphosphate–dependent chromatin-remodeling protein CHD4 (chromodomain helicase DNA-binding protein 4) as a factor that becomes transiently immobilized on chromatin after IR. Knockdown of CHD4 triggers enhanced Cdc25A degradation and p21Cip1 accumulation, which lead to more pronounced cyclin-dependent kinase inhibition and extended cell cycle delay. At DNA double-strand breaks, depletion of CHD4 disrupts the chromatin response at the level of the RNF168 ubiquitin ligase, which in turn impairs local ubiquitylation and BRCA1 assembly. These cell cycle and chromatin defects are accompanied by elevated spontaneous and IR-induced DNA breakage, reduced efficiency of DNA repair, and decreased clonogenic survival. Thus, CHD4 emerges as a novel genome caretaker and a factor that facilitates both checkpoint signaling and repair events after DNA damage.

scholarly journals Genome-wide CRISPR screen reveals host genes that regulate SARS-CoV-2 infection

2020 ◽  
Author(s):  
Jin Wei ◽  
Mia Madel Alfajaro ◽  
Ruth E. Hanna ◽  
Peter C. DeWeirdt ◽  
Madison S. Strine ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Cathepsin L ◽  
Therapeutic Targets ◽  
Chromatin Remodeling Complex ◽  
Genome Wide ◽  
A Genome ◽  
Viral Genes ◽  
Crispr Screen ◽  
Chaperone Complex ◽  
Host Genes

Identification of host genes essential for SARS-CoV-2 infection may reveal novel therapeutic targets and inform our understanding of COVID-19 pathogenesis. Here we performed a genome-wide CRISPR screen with SARS-CoV-2 and identified known SARS-CoV-2 host factors including the receptor ACE2 and protease Cathepsin L. We additionally discovered novel pro-viral genes and pathways including the SWI/SNF chromatin remodeling complex and key components of the TGF-β signaling pathway. Small molecule inhibitors of these pathways prevented SARS-CoV-2-induced cell death. We also revealed that the alarmin HMGB1 is critical for SARS-CoV-2 replication. In contrast, loss of the histone H3.3 chaperone complex sensitized cells to virus-induced death. Together this study reveals potential therapeutic targets for SARS-CoV-2 and highlights host genes that may regulate COVID-19 pathogenesis.

scholarly journals Actin-Related Protein 6 (Arp6) Influences Double-Strand Break Repair in Yeast

2021 ◽  
Vol 1 (2) ◽  
pp. 225-238
Author(s):  
Mohsen Hooshyar ◽  
Daniel Burnside ◽  
Maryam Hajikarimlou ◽  
Katayoun Omidi ◽  
Alexander Jesso ◽  
...  
Keyword(s):  
Dna Damage ◽  
Chromatin Remodeling ◽  
Genetic Interaction ◽  
Interaction Analysis ◽  
Strand Break ◽  
Dna Double Strand Breaks ◽  
Dsb Repair ◽  
Dna Damaging Agents ◽  
Repair Efficiency ◽  
Chromosomal Breaks

DNA double-strand breaks (DSBs) are the most deleterious form of DNA damage and are repaired through non-homologous end-joining (NHEJ) or homologous recombination (HR). Repair initiation, regulation and communication with signaling pathways require several histone-modifying and chromatin-remodeling complexes. In budding yeast, this involves three primary complexes: INO80-C, which is primarily associated with HR, SWR1-C, which promotes NHEJ, and RSC-C, which is involved in both pathways as well as the general DNA damage response. Here we identify ARP6 as a factor involved in DSB repair through an RSC-C-related pathway. The loss of ARP6 significantly reduces the NHEJ repair efficiency of linearized plasmids with cohesive ends, impairs the repair of chromosomal breaks, and sensitizes cells to DNA-damaging agents. Genetic interaction analysis indicates that ARP6, MRE11 and RSC-C function within the same pathway, and the overexpression of ARP6 rescues rsc2∆ and mre11∆ sensitivity to DNA-damaging agents. Double mutants of ARP6, and members of the INO80 and SWR1 complexes, cause a significant reduction in repair efficiency, suggesting that ARP6 functions independently of SWR1-C and INO80-C. These findings support a novel role for ARP6 in DSB repair that is independent of the SWR1 chromatin remodeling complex, through an apparent RSC-C and MRE11-associated DNA repair pathway.

scholarly journals Emerging Technologies for Genome-Wide Profiling of DNA Breakage

2021 ◽  
Vol 11 ◽  
Author(s):  
Matthew J. Rybin ◽  
Melina Ramic ◽  
Natalie R. Ricciardi ◽  
Philipp Kapranov ◽  
Claes Wahlestedt ◽  
...  
Keyword(s):  
Genome Instability ◽  
Dna Double Strand Breaks ◽  
Single Nucleotide ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Genome Wide ◽  
A Genome ◽  
Wide Scale ◽  
Nucleotide Resolution ◽  
Genomic Regions

Genome instability is associated with myriad human diseases and is a well-known feature of both cancer and neurodegenerative disease. Until recently, the ability to assess DNA damage—the principal driver of genome instability—was limited to relatively imprecise methods or restricted to studying predefined genomic regions. Recently, new techniques for detecting DNA double strand breaks (DSBs) and single strand breaks (SSBs) with next-generation sequencing on a genome-wide scale with single nucleotide resolution have emerged. With these new tools, efforts are underway to define the “breakome” in normal aging and disease. Here, we compare the relative strengths and weaknesses of these technologies and their potential application to studying neurodegenerative diseases.

scholarly journals Efg1-mediated Recruitment of NuA4 to Promoters Is Required for Hypha-specific Swi/Snf Binding and Activation inCandida albicans

2008 ◽  
Vol 19 (10) ◽  
pp. 4260-4272 ◽  
Author(s):  
Yang Lu ◽  
Chang Su ◽  
Xuming Mao ◽  
Prashna Pala Raniga ◽  
Haoping Liu ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Transcriptional Activation ◽  
Chromatin Immunoprecipitation ◽  
Pathogenic Fungus ◽  
Dependent Manner ◽  
Hyphal Development ◽  
Chromatin Remodeling Complex ◽  
A Subunit ◽  
Human Pathogenic Fungus ◽  
Incandida Albicans

Efg1 is essential for hyphal development and virulence in the human pathogenic fungus Candida albicans. How Efg1 regulates gene expression is unknown. Here, we show that Efg1 interacts with components of the nucleosome acetyltransferase of H4 (NuA4) histone acetyltransferase (HAT) complex in both yeast and hyphal cells. Deleting YNG2, a subunit of the NuA4 HAT module, results in a significant decrease in the acetylation level of nucleosomal H4 and a profound defect in hyphal development, as well as a defect in the expression of hypha-specific genes. Using chromatin immunoprecipitation, Efg1 and the NuA4 complex are found at the UAS regions of hypha-specific genes in both yeast and hyphal cells, and Efg1 is required for the recruitment of NuA4. Nucleosomal H4 acetylation at the promoters peaks during initial hyphal induction in an Efg1-dependent manner. We also find that Efg1 bound to the promoters of hypha-specific genes is critical for recruitment of the Swi/Snf chromatin remodeling complex during hyphal induction. Our data show that the recruitment of the NuA4 complex by Efg1 to the promoters of hypha-specific genes is required for nucleosomal H4 acetylation at the promoters during hyphal induction and for subsequent binding of Swi/Snf and transcriptional activation.

scholarly journals RSC2, Encoding a Component of the RSC Nucleosome Remodeling Complex, Is Essential for 2μm Plasmid Maintenance in Saccharomyces cerevisiae

2002 ◽  
Vol 22 (12) ◽  
pp. 4218-4229 ◽  
Author(s):  
Michael C. V. L. Wong ◽  
Suzanna R. S. Scott-Drew ◽  
Matthew J. Hayes ◽  
Philip J. Howard ◽  
James A. H. Murray
Keyword(s):  
Chromatin Remodeling ◽  
Chromatin Structure ◽  
Plasmid Dna ◽  
Direct Evidence ◽  
Maternal Inheritance ◽  
Alternative Form ◽  
Nucleosome Remodeling ◽  
Daughter Cells ◽  
Chromatin Remodeling Complex ◽  
Stable Maintenance

ABSTRACT The stable maintenance of the 2μm circle plasmid depends on its ability to overcome intrinsic maternal inheritance bias, which in yeast normally results in the failure to transmit DNA molecules efficiently to daughter cells. In addition to the plasmid proteins Rep1 and Rep2 acting on the plasmid DNA locus STB, it is likely that other chromosomally encoded yeast proteins are required. We have isolated mutants of yeast unable to maintain 2μm and found that RSC2 is essential for 2μm to overcome maternal inheritance bias. Rsc2 is part of a multisubunit RSC chromatin remodeling complex, and we show that in the absence of Rsc2 the chromatin structure of the STB region is significantly altered and the Rep1 protein loses its normal localization to subnuclear foci. Rsc1, a closely related homolog of Rsc2 present in an alternative form of the RSC complex, is not required for 2μm maintenance and does not replace the requirement for Rsc2 when overexpressed. This represents the first specific role for Rsc2 that has been related to a change in chromatin structure, as well as the first direct evidence linking chromatin structure to 2μm segregation.

scholarly journals Sustained CHK2 activity, but not ATM activity, is critical to maintain a G1 arrest after DNA damage in untransformed cells

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Iraia García-Santisteban ◽  
Alba Llopis ◽  
Lenno Krenning ◽  
Jon Vallejo-Rodríguez ◽  
Bram van den Broek ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Cycle Progression ◽  
Double Strand Breaks ◽  
G1 Arrest ◽  
Dna Double Strand Breaks ◽  
Independent Manner ◽  
Cycle Progression ◽  
Strand Breaks ◽  
G1 Checkpoint ◽  
The Impact

Abstract Background The G1 checkpoint is a critical regulator of genomic stability in untransformed cells, preventing cell cycle progression after DNA damage. DNA double-strand breaks (DSBs) recruit and activate ATM, a kinase which in turn activates the CHK2 kinase to establish G1 arrest. While the onset of G1 arrest is well understood, the specific role that ATM and CHK2 play in regulating G1 checkpoint maintenance remains poorly characterized. Results Here we examine the impact of ATM and CHK2 activities on G1 checkpoint maintenance in untransformed cells after DNA damage caused by DSBs. We show that ATM becomes dispensable for G1 checkpoint maintenance as early as 1 h after DSB induction. In contrast, CHK2 kinase activity is necessary to maintain the G1 arrest, independently of ATM, ATR, and DNA-PKcs, implying that the G1 arrest is maintained in a lesion-independent manner. Sustained CHK2 activity is achieved through auto-activation and its acute inhibition enables cells to abrogate the G1-checkpoint and enter into S-phase. Accordingly, we show that CHK2 activity is lost in cells that recover from the G1 arrest, pointing to the involvement of a phosphatase with fast turnover. Conclusion Our data indicate that G1 checkpoint maintenance relies on CHK2 and that its negative regulation is crucial for G1 checkpoint recovery after DSB induction.

scholarly journals Sfh1p, a component of a novel chromatin-remodeling complex, is required for cell cycle progression.

1997 ◽  
Vol 17 (6) ◽  
pp. 3323-3334 ◽  
Author(s):  
Y Cao ◽  
B R Cairns ◽  
R D Kornberg ◽  
B C Laurent
Keyword(s):  
Cell Cycle ◽  
Chromatin Remodeling ◽  
Cell Cycle Progression ◽  
Normal Function ◽  
Temperature Sensitive ◽  
Cycle Progression ◽  
Conserved Domain ◽  
Chromatin Remodeling Complex ◽  
Evolutionarily Conserved ◽  
M Phase

Several eukaryotic multiprotein complexes, including the Saccharomyces cerevisiae Snf/Swi complex, remodel chromatin for transcription. In contrast to the Snf/Swi proteins, Sfh1p, a new Snf5p paralog, is essential for viability. The evolutionarily conserved domain of Sfh1p is sufficient for normal function, and Sfh1p interacts functionally and physically with an essential Snf2p paralog in a novel nucleosome-restructuring complex called RSC (for remodels the structure of chromatin). A temperature-sensitive sfh1 allele arrests cells in the G2/M phase of the cell cycle, and the Sfh1 protein is specifically phosphorylated in the G1 phase. Together, these results demonstrate a link between chromatin remodeling and progression through the cell division cycle, providing genetic clues to possible targets for RSC function.

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