Histone H3 Lysine 9 Acetylation Obstructs ATM Activation and Promotes Ionizing Radiation Sensitivity in Normal Stem Cells

Meyer, Barbara; Fabbrizi, Maria Rita; Raj, Suyash; Zobel, Cheri L.; Hallahan, Dennis E.; Sharma, Girdhar G.

doi:10.1016/j.stemcr.2016.11.004

Cited by 30 publications

(45 citation statements)

References 25 publications

(42 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because H3K9ac is frequently associated with transcriptionally active areas ( Lawrence et al., 2016 ), it is logical that in the event of DNA damage, it would be undesirable to collect a large body of repair factors while the transcription machinery is still local and active. Accordingly, in response to DNA damage, H3K9Ac becomes diminished at promoter regions of cell-cycle-responsive and active gene sites and at the sites of DNA lesions ( Tjeertes et al., 2009 , Bártová et al., 2011 , Meyer et al., 2016 ). Here, we also showed that H3K9ac decreases following H 2 O 2 treatment in human cells.…”

Section: Discussionmentioning

confidence: 99%

Interplay of Histone Marks with Serine ADP-Ribosylation

et al. 2018

View full text Add to dashboard Cite

SummarySerine ADP-ribosylation (Ser-ADPr) is a recently discovered protein modification that is catalyzed by PARP1 and PARP2 when in complex with the eponymous histone PARylation factor 1 (HPF1). In addition to numerous other targets, core histone tails are primary acceptors of Ser-ADPr in the DNA damage response. Here, we show that specific canonical histone marks interfere with Ser-ADPr of neighboring residues and vice versa. Most notably, acetylation, but not methylation of H3K9, is mutually exclusive with ADPr of H3S10 in vitro and in vivo. We also broaden the O-linked ADPr spectrum by providing evidence for tyrosine ADPr on HPF1 and other proteins. Finally, we facilitate wider investigations into the interplay of histone marks with Ser-ADPr by introducing a simple approach for profiling posttranslationally modified peptides. Our findings implicate Ser-ADPr as a dynamic addition to the complex interplay of modifications that shape the histone code.

show abstract

Section: Discussionmentioning

confidence: 99%

Interplay of Histone Marks with Serine ADP-Ribosylation

et al. 2018

View full text Add to dashboard Cite

show abstract

“…The strong heterochromatic structure as well as the quiescence of the HFSCs result in a high radio resistance in comparison with other stem cell pools . However, despite the high radio resistance, even LDR induces critical consequences for the stem cell pool with wide‐ranging effects on the whole organ .…”

Section: Resultsmentioning

confidence: 99%

Hair Follicle Stem Cell Faith Is Dependent on Chromatin Remodeling Capacity Following Low-Dose Radiation

2018

View full text Add to dashboard Cite

The main function of the skin, to protect against the environment, is supported by the activity of different stem cell populations. The main focus of this study was elucidating the coping mechanisms of stem cells against the stimulation of constant exposure to genotoxic stresses, both endogenous and exogenous, to ensure long-term function. Investigation of various mouse strains, differing in their DNA repair capacity, enables us to clarify fractionated low-dose irradiation (LDR)-induced consequences for different stem cell populations of the murine hair follicle (HF) in their physiological stem cell niche. Using microscopic techniques combined with flow cytometry, we could show that LDR induces accumulation of persisting; pKu70-independent 53BP1-foci ("chromatin-alterations") in heterochromatic regions of the HF stem cells (HFSCs). These remaining chromatin-alterations result in varying stem cell consequences. CD34-positive HFSCs react by ataxia telangiectasia mutated-dependent, premature senescence, which correlates with global chromatin compaction, whereby apoptosis is prevented by the activity of DNA-dependent protein kinase catalytic subunit. However, distinctively highly damaged HFSCs seem to be sorted out of the niche by differentiation, transferring their chromatin-alterations to more proliferative G protein-coupled receptor 5-positive stem cells. Consequentially, the loss of basal HFSCs is compensated by increased proliferation within the stem cell pool. Despite the initial success of these mechanisms in stem cell population maintenance, the combined effect of the chromatin-alterations and the modification in stem cell pool composition may lead to downstream long-term functional loss of tissue or organs. Stem Cells 2018;36:574-588.

show abstract

“…Radiation-induced long-lived free radicals are thought to cause progressive damage to normal tissues. More recent molecular studies suggest that depletion of tissue stem cells and progenitor cells by radiation could lead to much greater cell loss and tissue damage [ 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

Impact of Unilateral Orbital Radiotherapy on the Structure and Function of Bilateral Human Meibomian Gland

Chen

Liu

et al. 2018

Journal of Ophthalmology

View full text Add to dashboard Cite

Background Radiotherapy (RT) has widely been used to treat ocular tumors, yet the impact of orbital radiation to the meibomian gland has rarely been studied. Our study aims at evaluating the bilateral meibomian gland structure and function 12 months after unilateral orbital RT in patients with ocular tumors. Methods An observational case-control study. A total of 10 eyes 12 months after unilateral orbital RT, 10 contralateral eyes, and 10 normal controls were enrolled. Meibomian gland loss (MGL), lipid layer thickness (LLT), tear film breakup time (TBUT), Schirmer I test, and cornea fluorescein staining were measured. Ocular Surface Disease Index (OSDI) of the RT patients was assessed and compared with normal controls. Results The cumulative median radiotherapy dosage for the patients was 45 (range: 30, 70) Gy. The OSDI score of the patients was significantly greater than the normal controls (22.92 (range: 10.42, 37.50) vs 6.25 (range: 2.08, 10.42), p ≤ 0.001). Significant differences of upper MGL, lower MGL, LLT, and TBUT were found between the diseased eyes and normal controls (37.79% (range: 12.87, 92.41) vs 12.63% (range: 6.13, 42.34), p=0.007; 61.31% (range: 44.67, 87.98) vs 15.53% (range: 7.65, 45.13), p ≤ 0.001; 40 ICU (range: 23, 100) vs 81.5 ICU (range: 54, 100), p=0.007; 3.5 s (range: 2, 8) vs 6.5 s (range: 5, 10), p=0.002). The upper MGL and TBUT of the contralateral eyes were also considerably damaged compared with normal controls. Lower eyelid MGL and cornea staining score of the diseased eye were significantly correlated with radiation dosage (r = 0.913 and 0.680; p=0.001 and 0.044, respectively). Conclusion Orbital radiotherapy could cause significant damage to the meibomian gland structure and function, not only the diseased eyes but also the contralateral eyes.

show abstract

Histone H3 Lysine 9 Acetylation Obstructs ATM Activation and Promotes Ionizing Radiation Sensitivity in Normal Stem Cells

Cited by 30 publications

References 25 publications

Interplay of Histone Marks with Serine ADP-Ribosylation

Interplay of Histone Marks with Serine ADP-Ribosylation

Hair Follicle Stem Cell Faith Is Dependent on Chromatin Remodeling Capacity Following Low-Dose Radiation

Impact of Unilateral Orbital Radiotherapy on the Structure and Function of Bilateral Human Meibomian Gland

Contact Info

Product

Resources

About