scholarly journals Histone demethylase KDM5A regulates the ZMYND8–NuRD chromatin remodeler to promote DNA repair

2017 ◽  
Vol 216 (7) ◽  
pp. 1959-1974 ◽  
Author(s):  
Fade Gong ◽  
Thomas Clouaire ◽  
Marion Aguirrebengoa ◽  
Gaëlle Legube ◽  
Kyle M. Miller
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Transcriptional Silencing ◽  
Strand Break ◽  
Histone Demethylase ◽  
Histone Deacetylation ◽  
Nucleosome Remodeling ◽  
Dna Damage Signaling ◽  
Dna Double Strand Break ◽  
Damage Response

Upon DNA damage, histone modifications are dynamically reshaped to accommodate DNA damage signaling and repair within chromatin. In this study, we report the identification of the histone demethylase KDM5A as a key regulator of the bromodomain protein ZMYND8 and NuRD (nucleosome remodeling and histone deacetylation) complex in the DNA damage response. We observe KDM5A-dependent H3K4me3 demethylation within chromatin near DNA double-strand break (DSB) sites. Mechanistically, demethylation of H3K4me3 is required for ZMYND8–NuRD binding to chromatin and recruitment to DNA damage. Functionally, KDM5A deficiency results in impaired transcriptional silencing and repair of DSBs by homologous recombination. Thus, this study identifies a crucial function for KDM5A in demethylating H3K4 to allow ZMYND8–NuRD to operate within damaged chromatin to repair DSBs.

scholarly journals Schizosaccharomyces pombe KAT5 contributes to resection and repair of a DNA double strand break

Genetics ◽  
2021 ◽  
Author(s):  
Tingting Li ◽  
Ruben C Petreaca ◽  
Susan L Forsburg
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Chromatin Remodeling ◽  
Dna Damage Response ◽  
Histone Acetyltransferase ◽  
Strand Break ◽  
Double Strand Break ◽  
Dna Damage Checkpoint ◽  
Dna Double Strand Break ◽  
Damage Response

Abstract Chromatin remodeling is essential for effective repair of a DNA double strand break. KAT5 (S. pombe Mst1, human TIP60) is a MYST family histone acetyltransferase conserved from yeast to humans that coordinates various DNA damage response activities at a DNA double strand break (DSB), including histone remodeling and activation of the DNA damage checkpoint. In S. pombe, mutations in mst1+ causes sensitivity to DNA damaging drugs. Here we show that Mst1 is recruited to DSBs. Mutation of mst1+ disrupts recruitment of repair proteins and delays resection. These defects are partially rescued by deletion of pku70, which has been previously shown to antagonize repair by homologous recombination. These phenotypes of mst1 are similar to pht1-4KR, a non-acetylatable form of histone variant H2A.Z, which has been proposed to affect resection. Our data suggest that Mst1 functions to direct repair of DSBs towards homologous recombination pathways by modulating resection at the double strand break.

scholarly journals DNA Damage-Induced Phosphorylation of TRF2 Is Required for the Fast Pathway of DNA Double-Strand Break Repair

2009 ◽  
Vol 29 (13) ◽  
pp. 3597-3604 ◽  
Author(s):  
Nazmul Huda ◽  
Hiromi Tanaka ◽  
Marc S. Mendonca ◽  
David Gilley
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Functional Role ◽  
Strand Break ◽  
Telomere Maintenance ◽  
Telomeric Dna ◽  
Dsb Repair ◽  
Dna Double Strand Break ◽  
Damage Response ◽  
Fast Pathway

ABSTRACT Protein kinases of the phosphatidylinositol 3-kinase-like kinase family, originally known to act in maintaining genomic integrity via DNA repair pathways, have been shown to also function in telomere maintenance. Here we focus on the functional role of DNA damage-induced phosphorylation of the essential mammalian telomeric DNA binding protein TRF2, which coordinates the assembly of the proteinaceous cap to disguise the chromosome end from being recognized as a double-stand break (DSB). Previous results suggested a link between the transient induction of human TRF2 phosphorylation at threonine 188 (T188) by the ataxia telangiectasia mutated protein kinase (ATM) and the DNA damage response. Here, we report evidence that X-ray-induced phosphorylation of TRF2 at T188 plays a role in the fast pathway of DNA DSB repair. These results connect the highly transient induction of human TRF2 phosphorylation to the DNA damage response machinery. Thus, we find that a protein known to function in telomere maintenance, TRF2, also plays a functional role in DNA DSB repair.

Variants in DNA double-strand break repair and DNA damage-response genes and susceptibility to lung and head and neck cancers

2008 ◽  
Vol 123 (2) ◽  
pp. 457-463 ◽  
Author(s):  
Patrick Danoy ◽  
Stefan Michiels ◽  
Philippe Dessen ◽  
Cécile Pignat ◽  
Thomas Boulet ◽  
...  
Keyword(s):  
Dna Damage ◽  
Head And Neck ◽  
Dna Damage Response ◽  
Strand Break ◽  
Double Strand Break ◽  
Head And Neck Cancers ◽  
Double Strand Break Repair ◽  
Dna Double Strand Break ◽  
Damage Response ◽  
Break Repair

Alkylator-Induced DNA Damage Response in Multiple Myeloma (MM) Cells Is Amplified by Histone Deacetylase (HDAC) Inhibition, Resulting in Significant Synergism in Cell Death

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5157-5157
Author(s):  
Choon Kee Lee ◽  
Shuiliang Wang ◽  
Xiaoping Huang ◽  
John Ryder ◽  
Peter Ordentlich ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Lines ◽  
Dna Damage Response ◽  
Strand Break ◽  
Mitotic Catastrophe ◽  
Hdac Inhibition ◽  
Dna Double Strand Break ◽  
Damage Response

Abstract One of the main mechanisms of action of HDAC inhibitors is the transcriptional reactivation of dormant tumor-suppressor genes through acetylation of histones, thereby inducing apoptosis. Treatment with HDACI has also been shown to induce chromatin destabilization in a transcription independent way. In the current study, we sought to determine whether HDAC inhibition induces DNA damage and amplifies alkylator-induced mitotic cell death in both melphalan sensitive- and resistant-MM cell lines (RPMI8226, 8226/LR5). The IC50 values of SNDX275, a class I HDACI agent, and melphalan on the 72-hour MTT assay were 268.05 nM and 245.94 nM in the RPMI8226, and 309.91 nM and 8657.46 nM in the 8226/LR5, respectively. When combined together at clinically attainable concentrations, the combination index by the Chou-Talalay method ranged from 0.27 to 0.75 for the RPMI8226 and from 0.33 to 0.7 for the 8226/LR5, indicating a powerful synergism. For elucidation of molecular mechanisms, MM1S and RPMI8226 cell lines were investigated for apoptosis, histone acetylation, cell cycle analysis, DNA double strand break and DNA damage response serially in 48-hour culture with SNDX-275 at 500 nM and melphalan at 10 μM, alone and in combination. Cleavage of PARP was seen following treatment with each SNDX275 and melphalan, but was highest at 48 hours with the combination of both. Apoptosis was associated with cleavage of caspases of 8, 3 and 9, which was most intense on combination. Melphalan amplified SNDX275-induced acetylation of H3. In cell cycle analysis by flow cytometry, SNDX275 caused an increase in G0-G1 and a decrease in S and G2-M. Cyclin D1, E2F-1 and p53 on western blot were not affected but expression of p21 increased. Melphalan arrested the cell cycle at G2, increased expression of p53 in the RPMI8226 and of p21 in the MM1S. The combination intensified the increase in p21 in both cell lines and in p53 only in the RPMI8226. Phosphorylation of H2AX, a marker of DNA double strand break, increased in a time dependent manner following each drug, along with an increase in phosphorylation of CHK1 and CHK2, indicative of initiation of DNA damage response. The increase in γH2AX and pCHK1 & 2, however, was considerably higher on combination than each drug alone. Furthermore, morphologic assessment of dead cells by the 48 hours of culture revealed a significant increase in mitotic catastrophe on combination in the MM1S: 0% on SNDX275 alone; 10% on melphalan alone; 43.4% on combination. The current study suggests that HDAC inhibition synergizes with melphalan in MM cells and that intensification of DNA damage is one of the mechanisms. Further studies are necessary to understand the role of HDAC inhibition for induction of mitotic catastrophe.

scholarly journals Schizosaccharomyces pombe KAT5 contributes to resection and repair of a DNA double strand break

2020 ◽  
Author(s):  
Tingting Li ◽  
Ruben C. Petreaca ◽  
Susan L. Forsburg
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Chromatin Remodeling ◽  
Dna Damage Response ◽  
Histone Acetyltransferase ◽  
Strand Break ◽  
Double Strand Break ◽  
Dna Damage Checkpoint ◽  
Dna Double Strand Break ◽  
Damage Response

AbstractChromatin remodeling is essential for effective repair of a DNA double strand break. KAT5 (S. pombe Mst1, human TIP60) is a MYST family histone acetyltransferase conserved from yeast to humans that coordinates various DNA damage response activities at a DSB, including histone remodeling and activation of the DNA damage checkpoint. In S. pombe, mutations in mst1+ causes sensitivity to DNA damaging drugs. Here we show that Mst1 is recruited to DSBs. Mutation of mst1+ disrupts recruitment of repair proteins and delays resection. These defects are partially rescued by deletion of pku70, which has been previously shown to antagonize repair by homologous recombination. These phenotypes of mst1 are similar to pht1-4KR, a non-acetylatable form of histone variant H2A.Z, which has been proposed to affect resection. These data suggest that Mst1 functions to direct repair of DSBs towards homologous recombination pathways by modulating resection at the double strand break.

scholarly journals Subsequent Neoplasm Risk Associated With Rare Variants in DNA Damage Response and Clinical Radiation Sensitivity Syndrome Genes in the Childhood Cancer Survivor Study

2020 ◽  
pp. 926-936
Author(s):  
Lindsay M. Morton ◽  
Danielle M. Karyadi ◽  
Stephen W. Hartley ◽  
Megan N. Frone ◽  
Joshua N. Sampson ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Survivors ◽  
Childhood Cancer ◽  
Dna Damage Response ◽  
Rare Variants ◽  
Childhood Cancer Survivors ◽  
Radiation Sensitivity ◽  
Strand Break ◽  
Dna Double Strand Break ◽  
Damage Response

PURPOSE Radiotherapy for childhood cancer is associated with elevated subsequent neoplasm (SN) risk, but the contribution of rare variants in DNA damage response and radiation sensitivity genes to SN risk is unknown. PATIENTS AND METHODS We conducted whole-exome sequencing in a cohort of childhood cancer survivors originally diagnosed during 1970 to 1986 (mean follow-up, 32.7 years), with reconstruction of doses to body regions from radiotherapy records. We identified patients who developed SN types previously reported to be related to radiotherapy (RT-SNs; eg, basal cell carcinoma [BCC], breast cancer, meningioma, thyroid cancer, sarcoma) and matched controls (sex, childhood cancer type/diagnosis, age, SN location, radiation dose, survival). Conditional logistic regression assessed SN risk associated with potentially protein-damaging rare variants (SnpEff, ClinVar) in 476 DNA damage response or radiation sensitivity genes with exact permutation-based P values using a Bonferroni-corrected significance threshold of P < 8.06 × 10−5. RESULTS Among 5,105 childhood cancer survivors of European descent, 1,108 (21.7%) developed at least 1 RT-SN. Out-of-field RT-SN risk, excluding BCC, was associated with homologous recombination repair (HRR) gene variants (patient cases, 23.2%; controls, 10.8%; odds ratio [OR], 2.6; 95% CI, 1.7 to 3.9; P = 4.79 × 10−5), most notably but nonsignificantly for FANCM (patient cases, 4.0%; matched controls, 0.6%; P = 9.64 × 10−5). HRR variants were not associated with likely in/near-field RT-SNs, excluding BCC (patient cases, 12.7%; matched controls, 12.9%; P = .92). Irrespective of radiation dose, risk for RT-SNs was also associated with EXO1 variants (patient cases, 1.8%; controls, 0.4%; P = 3.31 × 10−5), another gene implicated in DNA double-strand break repair. CONCLUSION In this large-scale discovery study, we identified novel associations between RT-SN risk after childhood cancer and potentially protein-damaging rare variants in genes involved in DNA double-strand break repair, particularly HRR. With replication, these results could affect screening recommendations for childhood cancer survivors and risk-benefit assessments of treatment approaches.

scholarly journals Sites of Acetylation on Newly Synthesized Histone H4 Are Required for Chromatin Assembly and DNA Damage Response Signaling

2013 ◽  
Vol 33 (16) ◽  
pp. 3286-3298 ◽  
Author(s):  
Zhongqi Ge ◽  
Devi Nair ◽  
Xiaoyan Guan ◽  
Neha Rastogi ◽  
Michael A. Freitas ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Histone H3 ◽  
Model Organism ◽  
Strand Break ◽  
Chromatin Assembly ◽  
Histone H4 ◽  
Histone H4 Acetylation ◽  
Damage Response ◽  
A Site

The best-characterized acetylation of newly synthesized histone H4 is the diacetylation of the NH2-terminal tail on lysines 5 and 12. Despite its evolutionary conservation, this pattern of modification has not been shown to be essential for either viability or chromatin assembly in any model organism. We demonstrate that mutations in histone H4 lysines 5 and 12 in yeast confer hypersensitivity to replication stress and DNA-damaging agents when combined with mutations in histone H4 lysine 91, which has also been found to be a site of acetylation on soluble histone H4. In addition, these mutations confer a dramatic decrease in cell viability when combined with mutations in histone H3 lysine 56. We also show that mutation of the sites of acetylation on newly synthesized histone H4 results in defects in the reassembly of chromatin structure that accompanies the repair of HO-mediated double-strand breaks. This defect is not due to a decrease in the level of histone H3 lysine 56 acetylation. Intriguingly, mutations that alter the sites of newly synthesized histone H4 acetylation display a marked decrease in levels of phosphorylated H2A (γ-H2AX) in chromatin surrounding the double-strand break. These results indicate that the sites of acetylation on newly synthesized histones H3 and H4 can function in nonoverlapping ways that are required for chromatin assembly, viability, and DNA damage response signaling.

scholarly journals NF-κB-dependent DNA damage-signaling differentially regulates DNA double-strand break repair mechanisms in immature and mature human hematopoietic cells

Leukemia ◽  
2015 ◽  
Vol 29 (7) ◽  
pp. 1543-1554 ◽  
Author(s):  
D Kraft ◽  
M Rall ◽  
M Volcic ◽  
E Metzler ◽  
A Groo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Hematopoietic Cells ◽  
Strand Break ◽  
Double Strand Break ◽  
Double Strand Break Repair ◽  
Dna Damage Signaling ◽  
Dna Double Strand Break ◽  
Repair Mechanisms ◽  
Break Repair
Sign in / Sign up

Export Citation Format

Share Document