Histone Acetyltransferase MOF Orchestrates Outcomes at the Crossroad of Oncogenesis, DNA Damage Response, Proliferation, and Stem Cell Development

ABSTRACT The DNA and protein complex known as chromatin is subject to posttranslational modifications (PTMs) that regulate cellular functions such that PTM dysregulation can lead to disease, including cancer. One critical PTM is acetylation/deacetylation, which is being investigated as a means to develop targeted cancer therapies. The histone acetyltransferase (HAT) family of proteins performs histone acetylation. In humans, MOF (hMOF), a member of the MYST family of HATs, acetylates histone H4 at lysine 16 (H4K16ac). MOF-mediated acetylation plays a critical role in the DNA damage response (DDR) and embryonic stem cell development. Functionally, MOF is found in two distinct complexes: NSL (nonspecific lethal) in humans and MSL (male-specific lethal) in flies. The NSL complex is also able to acetylate additional histone H4 sites. Dysregulation of MOF activity occurs in multiple cancers, including ovarian cancer, medulloblastoma, breast cancer, colorectal cancer, and lung cancer. Bioinformatics analysis of KAT8, the gene encoding hMOF, indicated that it is highly overexpressed in kidney tumors as part of a concerted gene coexpression program that can support high levels of chromosome segregation and cell proliferation. The linkage between MOF and tumor proliferation suggests that there are additional functions of MOF that remain to be discovered.

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Abstract 518: Ionizing radiation-induced DNA damage response decreases during induced pluripotent and embryonic stem cell differentiation

10.1158/1538-7445.am2016-518 ◽

2016 ◽

Author(s):

Kalpana Mujoo ◽

Raj K. Pandita ◽

Anjana Tiwari ◽

Vijay Charaka ◽

Walter N. Hittelman ◽

...

Keyword(s):

Dna Damage ◽

Stem Cell ◽

Cell Differentiation ◽

Dna Damage Response ◽

Embryonic Stem ◽

Stem Cell Differentiation ◽

Embryonic Stem Cell Differentiation ◽

Damage Response ◽

Radiation Induced ◽

Induced Pluripotent

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

Molecular and Cellular Biology ◽

10.1128/mcb.00460-13 ◽

2013 ◽

Vol 33 (16) ◽

pp. 3286-3298 ◽

Cited By ~ 19

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.

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Pseudorabies virus infection triggers NF-κB activation via the DNA damage response, but actively inhibits NFkB-dependent gene expression

Journal of Virology ◽

10.1128/jvi.01666-21 ◽

2021 ◽

Author(s):

Nicolás Romero ◽

Herman W. Favoreel

Keyword(s):

Gene Expression ◽

Dna Damage ◽

Dna Damage Response ◽

Pseudorabies Virus ◽

Critical Role ◽

Genome Replication ◽

Viral Protein Synthesis ◽

Damage Response ◽

Signaling Axis ◽

Inside Out

The nuclear factor kappa B (NF-κB) pathway is known to integrate signaling associated with very diverse intra- and extracellular stressors including virus infections, and triggers a powerful (pro-inflammatory) response through the expression of NF-κB-regulated genes. Typically, the NF-κB pathway collects and transduces threatening signals at the cell surface or in the cytoplasm leading to nuclear import of activated NF-κB transcription factors. In the current work, we demonstrate that the swine alphaherpesvirus pseudorabies virus (PRV) induces a peculiar mode of NF-κB activation known as “inside-out” NF-κB activation. We show that PRV triggers the DNA damage response (DDR) and that this DDR response drives NF-κB activation since inhibition of the nuclear ataxia telangiectasia-mutated (ATM) kinase, a chief controller of DDR, abolished PRV-induced NF-κB activation. Initiation of the DDR-NF-κB signaling axis requires viral protein synthesis but occurs before active viral genome replication. In addition, the initiation of the DDR-NF-κB signaling axis is followed by a virus-induced complete shutoff of NF-κB-dependent gene expression that depends on viral DNA replication. In summary, the results presented in this study reveal that PRV infection triggers a non-canonical DDR-NF-κB activation signaling axis and that the virus actively inhibits the (potentially antiviral) consequences of this pathway, by inhibiting NF-κB-dependent gene expression. IMPORTANCE: The NF-κB signaling pathway plays a critical role in coordination of innate immune responses that are of vital importance in the control of infections. The current report generates new insights in the interaction of the alphaherpesvirus pseudorabies virus (PRV) with the NF-κB pathway, as they reveal that (i) PRV infection leads to NF-κB activation via a peculiar “inside-out’ nucleus-to-cytoplasm signal that is triggered via the DNA damage response (DDR), (ii) the DDR-NF-κB signaling axis requires expression of viral proteins but is initiated before active PRV replication, and (iii) late viral factor(s) allow PRV to actively and efficiently inhibit NF-κB-dependent (pro-inflammatory) gene expression. These data suggest that activation of the DDR-NF-κB during PRV infection is host-driven and that its potential antiviral consequences are actively inhibited by the virus.

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

Genetics ◽

10.1093/genetics/iyab042 ◽

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.

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Role of the circadian clock "Death-Loop" in the DNA damage response underpinning cancer treatment resistance

10.1101/2022.01.14.476363 ◽

2022 ◽

Author(s):

Ninel Miriam Vainshelbaum ◽

Kristine Salmina ◽

Bogdan I Gerashchenko ◽

Marija Lazovska ◽

Pawel Zayakin ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Circadian Clock ◽

Cancer Cells ◽

Dna Damage Response ◽

Embryonic Stem ◽

Early Embryo ◽

Mitotic Slippage ◽

Damage Response ◽

Telomere Regulation

The Circadian Clock (CC) drives the normal cell cycle and reciprocally regulates telomere elongation. However, it can be deregulated in cancer, embryonic stem cells (ESC) and the early embryo. Here, its role in the resistance of cancer cells to genotoxic treatments was assessed in relation to whole-genome duplication (WGD) and telomere regulation. We first evaluated the DNA damage response of polyploid cancer cells and observed a similar impact on the cell cycle to that seen in ESC - overcoming G1/S, adapting DNA damage checkpoints, tolerating DNA damage, and coupling telomere erosion to accelerated cell senescence, favouring transition by mitotic slippage into the ploidy cycle (reversible polyploidy). Next, we revealed a positive correlation between cancer WGD and deregulation of CC assessed by bioinformatics on 11 primary cancer datasets (rho=0.83; p<0.01). As previously shown, the cancer cells undergoing mitotic slippage cast off telomere fragments with TERT, restore the telomeres by recombination and return their depolyploidised mitotic offspring to TERT-dependent telomere regulation. Through depolyploidisation and the CC "death loop", the telomeres and Hayflick limit count are thus again renewed. This mechanism along with similar inactivity of the CC in early embryos supports a life-cycle (embryonic) concept of cancer.

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