Inhibition of Histone Deacetylase 3 Causes Replication Stress in Cutaneous T Cell Lymphoma

Wells, Christina E.; Bhaskara, Srividya; Stengel, Kristy R.; Zhao, Yue; Sirbu, Bianca M.; Chagot, Benjamin; Chen, David; Khabele, Dineo; Chazin, Walter J.; Cooper, Andrea; Jacques, Vincent; Rusche, James R.; Eischen, Christine M.; McGirt, Laura Y.; Hiebert, Scott W.

doi:10.1371/journal.pone.0068915

Cited by 89 publications

(82 citation statements)

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“…Replication stress might be a consequence of impaired NHEJ, as has been reported previously (Saintigny et al , 2001; Lundin et al , 2002). However, we cannot rule out that SIRT7 might have an effect on chromatin structure at the replication fork, which has been suggested for other histone deacetylases (Bhaskara et al , 2013; Wells et al , 2013), and/or by directly targeting the DNA replication machinery. Therefore, the increase genome instability in SIRT7‐depleted cells could be due to a cumulative effect of replication stress and the failure to repair fork‐associated DNA damage.…”

Section: Discussionmentioning

confidence: 83%

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

et al. 2016

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Sirtuins, a family of protein deacetylases, promote cellular homeostasis by mediating communication between cells and environment. The enzymatic activity of the mammalian sirtuin SIRT7 targets acetylated lysine in the N‐terminal tail of histone H3 (H3K18Ac), thus modulating chromatin structure and transcriptional competency. SIRT7 deletion is associated with reduced lifespan in mice through unknown mechanisms. Here, we show that SirT7‐knockout mice suffer from partial embryonic lethality and a progeroid‐like phenotype. Consistently, SIRT7‐deficient cells display increased replication stress and impaired DNA repair. SIRT7 is recruited in a PARP1‐dependent manner to sites of DNA damage, where it modulates H3K18Ac levels. H3K18Ac in turn affects recruitment of the damage response factor 53BP1 to DNA double‐strand breaks (DSBs), thereby influencing the efficiency of non‐homologous end joining (NHEJ). These results reveal a direct role for SIRT7 in DSB repair and establish a functional link between SIRT7‐mediated H3K18 deacetylation and the maintenance of genome integrity.

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Section: Discussionmentioning

confidence: 83%

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

et al. 2016

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“…In cutaneous T-cell lymphoma (CTCL) cell lines treated with both broad-spectrum and HDAC3-selective inhibitors, the effects of HDI treatment on replication fork velocity were observed before the accumulation of global increases in histone acetylation (128). These results suggest that HDACs function to regulate replication (or local chromatin structure) on or around the replication fork.…”

Section: Figmentioning

confidence: 99%

“…Remarkably, HDACs 1-3 deacetylate many of the same residues on the histone tails, including H3K4, H3K9, H3K14, H3K27, H4K5, H4K8, H4K12, and H4K16 (13,131). The lone exception appears to be H3K56ac, which is affected by inactivation of Hdac1 and Hdac2, but not Hdac3 (76,128). The acetylation of specific histone lysines may have unique functions.…”

Section: Fig 2 Recruitment Of Hdac-containing Repressormentioning

confidence: 99%

“…While such general changes in chromatin architecture may play a role in the generation of replication stress after HDAC inhibition, disruption of HDAC functions may also directly affect replication, as very short treatment with histone deacetylase inhibitors (HDIs) still generated robust reductions in the rates of replication fork progression (112,128). In cutaneous T-cell lymphoma (CTCL) cell lines treated with both broad-spectrum and HDAC3-selective inhibitors, the effects of HDI treatment on replication fork velocity were observed before the accumulation of global increases in histone acetylation (128).…”

Section: Figmentioning

confidence: 99%

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Class I HDACs Affect DNA Replication, Repair, and Chromatin Structure: Implications for Cancer Therapy

Stengel

Hiebert

2015

Antioxidants & Redox Signaling

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Significance: The contribution of epigenetic alterations to cancer development and progression is becoming increasingly clear, prompting the development of epigenetic therapies. Histone deacetylase inhibitors (HDIs) represent one of the first classes of such therapy. Two HDIs, Vorinostat and Romidepsin, are broad-spectrum inhibitors that target multiple histone deacetylases (HDACs) and are FDA approved for the treatment of cutaneous T-cell lymphoma. However, the mechanism of action and the basis for the cancer-selective effects of these inhibitors are still unclear. Recent Advances: While the anti-tumor effects of HDIs have traditionally been attributed to their ability to modify gene expression after the accumulation of histone acetylation, recent studies have identified the effects of HDACs on DNA replication, DNA repair, and genome stability. In addition, the HDIs available in the clinic target multiple HDACs, making it difficult to assign either their anti-tumor effects or their associated toxicities to the inhibition of a single protein. However, recent studies in mouse models provide insights into the tissue-specific functions of individual HDACs and their involvement in mediating the effects of HDI therapy. Critical Issues: Here, we describe how altered replication contributes to the efficacy of HDAC-targeted therapies as well as discuss what knowledge mouse models have provided to our understanding of the specific functions of class I HDACs, their potential involvement in tumorigenesis, and how their disruption may contribute to toxicities associated with HDI treatment. Future Directions: Impairment of DNA replication by HDIs has important therapeutic implications. Future studies should assess how best to exploit these findings for therapeutic gain. Antioxid. Redox Signal. 23, 51-65.

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“…In human T-cell lymphoma cells, HDAC3 accumulates around replication forks in a manner that shows a link between acetylation state and newly synthesized DNA; HDAC3 inhibition resulted in repression of replication fork progression and induced apoptosis with increased γ-H2AX and an S-phase defect (Wells et al, 2013). In the case of H3-K56 of yeast, acetylation is required to complete replication in the presence of lesions caused by methylmethane sulfonate (MMS) (Wurtele et al, 2012), and yeast cells defective in both CLR4 and SET2 (methyltransferases for H3-K9 and H3-K36, respectively) showed decreased RAD3 (fission yeast homolog of ATR)-dependent phosphorylation of CDC2 and MIK1 following hydroxyurea treatment, suggesting that hydroxyureainduced replication stress checkpoints require H3 methylation by CLR4 and SET2 (Kim et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Chromatin modification and NBS1: their relationship in DNA double-strand break repair

2015

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The importance of chromatin modification, including histone modification and chromatin remodeling, for DNA double-strand break (DSB) repair, as well as transcription and replication, has been elucidated. Phosphorylation of H2AX to γ-H2AX is one of the first responses following DSB detection, and this histone modification is important for the DSB damage response by triggering several events, including the accumulation of DNA damage response-related proteins and subsequent homologous recombination (HR) repair. The roles of other histone modifications such as acetylation, methylation and ubiquitination have also been recently clarified, particularly in the context of HR repair. NBS1 is a multifunctional protein that is involved in various DNA damage responses. Its recently identified binding partner RNF20 is an E3 ubiquitin ligase that facilitates the monoubiquitination of histone H2B, a process that is crucial for recruitment of the chromatin remodeler SNF2h to DSB damage sites. Evidence suggests that SNF2h functions in HR repair, probably through regulation of end-resection. Moreover, several recent reports have indicated that SNF2h can function in HR repair pathways as a histone remodeler and that other known histone remodelers can also participate in DSB damage responses. On the other hand, information about the roles of such chromatin modifications and NBS1 in non-homologous end joining (NHEJ) repair of DSBs and stalled fork-related damage responses is very limited; therefore, these aspects and processes need to be further studied to advance our understanding of the mechanisms and molecular players involved.

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Inhibition of Histone Deacetylase 3 Causes Replication Stress in Cutaneous T Cell Lymphoma

Cited by 89 publications

References 50 publications

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

Class I HDACs Affect DNA Replication, Repair, and Chromatin Structure: Implications for Cancer Therapy

Chromatin modification and NBS1: their relationship in DNA double-strand break repair

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