DNA-PK phosphorylates histone H2AX during apoptotic DNA fragmentation in mammalian cells

Mukherjee, Bipasha; Kessinger, Chase W.; Kobayashi, Junya; Chen, Benjamin P.C.; Chen, David J.; Chatterjee, A.; Burma, Sandeep

doi:10.1016/j.dnarep.2006.01.011

Cited by 181 publications

(148 citation statements)

References 70 publications

Supporting

Mentioning

131

Contrasting

Unclassified

Order By: Relevance

“…This links elevated H2AX phosphorylation with a decreased capacity for cellular reproduction after checkpoint abrogation. Other reports have made similar correlations with g-H2AX and apoptosis (27,49). Therefore, intense pan-nuclear staining of g-H2AX may signal that either DNA breaks are prevalent throughout the nucleus or DNA structure has been significantly compromised.…”

Section: Discussionmentioning

confidence: 50%

“…Depending on the nature of the DNA lesion, colocalization of g-H2AX can occur with other molecules, including 53BP1, Mre11, Rad50, and Nbs1, thus further suggesting its involvement in DNA repair (20,25). Recently, phosphorylation of H2AX has been shown to be required for the repair of double-strand breaks using sister chromatid recombination (26) and for DNA fragmentation during apoptosis (27,28). Dephosphorylation of H2AX by protein phosphatase 2A may be associated with efficient DNA repair (29).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

H2AX phosphorylation marks gemcitabine-induced stalled replication forks and their collapse upon S-phase checkpoint abrogation

Ewald

Sampath

Plunkett

2007

Molecular Cancer Therapeutics

187

172

View full text Add to dashboard Cite

Gemcitabine is a nucleoside analogue that is incorporated into replicating DNA, resulting in partial chain termination and stalling of replication forks. The histone variant H2AX is phosphorylated on Ser 139 (;-H2AX) and forms nuclear foci at sites of DNA damage. Here, we characterize the concentration-and time-dependent phosphorylation of H2AX in response to gemcitabine-induced stalled replication forks. The number of ;-H2AX foci increased with time up to 2 to 6 h after exposure to gemcitabine, whereas longer exposures did not cause greater phosphorylation or increase cell death. The percentage of ;-H2AX -positive cells increased with concentrations of gemcitabine up to 0.1 Mmol/L, and ;-H2AX was most evident in the S-phase fraction. Phosphorylation of ataxia-telangiectasia mutated (ATM) on Ser 1981 was also associated with S-phase cells and colocalized in the nucleus with phosphorylated H2AX foci after gemcitabine exposure.

show abstract

Section: Discussionmentioning

confidence: 50%

Section: Introductionmentioning

confidence: 99%

H2AX phosphorylation marks gemcitabine-induced stalled replication forks and their collapse upon S-phase checkpoint abrogation

Ewald

Sampath

Plunkett

2007

Molecular Cancer Therapeutics

187

172

View full text Add to dashboard Cite

show abstract

“…In line with this hypothesis, accumulation of DNA-PKcs, Ku70 and Ku80 following hypoxia and iron chelation have been demonstrated in a number of different cell lines (Ginis and Faller , 2000 ;Lynch et al , 2001 ;Um et al , 2004 ;Bouquet et al , 2011 ). DNA-PK has been shown to phosphorylate H2AX in different cell lines and in vivo in response to DNA damage (Stiff et al , 2004 ;Koike et al , 2008 ;An et al , 2010 ) under hypertonic conditions (Reitsema et al , 2005 ) and during apoptotic DNA fragmentation (Mukherjee et al , 2006 ). Of note, the hypoxic DNA-PK activation resulted in increased HIF-dependent gene expression (Bouquet et al , 2011 ).…”

Section: Discussionmentioning

confidence: 59%

HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia

Wrann

Kaufmann²,

Wirthner³

et al. 2013

Biological Chemistry

View full text Add to dashboard Cite

Abstract:The histone variant 2AX (H2AX) is phosphorylated at Serine 139 by the PI3K-like kinase family members ATM, ATR and DNA-PK. Genotoxic stress, such as tumor radioand chemotherapy, is considered to be the main inducer of phosphorylated H2AX ( γ H2AX), which forms distinct foci at sites of DNA damage where DNA repair factors accumulate. γ H2AX accumulation under severe hypoxic/anoxic (0.02 % oxygen) conditions has recently been reported to follow replication fork stalling in the absence of detectable DNA damage. In this study, we found HIF-dependent accumulation of γ H2AX in several cancer cell lines and mouse embryonic fibroblasts exposed to physiologically relevant chronic hypoxia (0.2 % oxygen), which did not induce detectable levels of DNA strand breaks. The hypoxic accumulation of γ H2AX was delayed by the RNAi-mediated knockdown of HIF-1 α or HIF-2 α and further decreased when both HIF-α s were absent. Conversely, basal phosphorylation of H2AX was increased in cells with constitutively stabilized HIF-2 α . These results suggest that both HIF-1 and HIF-2 are involved in γ H2AX accumulation by tumor hypoxia, which might increase a cancer cell ' s capacity to repair DNA damage, contributing to tumor therapy resistance.

show abstract

“…Protamines may act as a regulating checkpoint of spermatogenesis and alterations in the process of protamine substitution may lead to an apoptotic process that ends in severely diminished semen quality [Carrell et al, 2007]. Remarkably, phosphorylation of H2AX has been associated with the induction of apoptosis in somatic cells [Mukherjee et al, 2006]. To test the hypothesis that an apoptotic-like process is involved in delayed radiation-induced DNA fragmentation, we performed a time-course analysis of quantitative gene expression for five key pro-apoptotic genes between 7 and 45 days after irradiation.…”

Section: Discussionmentioning

confidence: 99%

Direct and delayed X‐ray‐induced DNA damage in male mouse germ cells

Cordelli¹,

Eleuteri²,

Grollino³

et al. 2012

Environ and Mol Mutagen

View full text Add to dashboard Cite

Sperm DNA integrity is essential for the accurate transmission of paternal genetic information. Various stages of spermatogenesis are characterized by large differences in radiosensitivity. Differentiating spermatogonia are susceptible to radiationinduced cell killing, but some of them can repair DNA damage and progress through differentiation. In this study, we applied the neutral comet assay, immunodetection of phosphorylated H2AX (g-H2AX) and the Sperm Chromatin Structure Assay (SCSA) to detect DNA strand breaks in testicular cells and spermatozoa at different times following in vivo X-ray irradiation. Radiation produced DNA strand breaks in testicular cells that were repaired within the first few hours after exposure. Spermatozoa were resistant to the induction of DNA damage, but non-targeted DNA lesions were detected in spermatozoa derived from surviving irradiated spermatogonia. These lesions formed while round spermatids started to elongate within the testicular seminiferous tubules. The transcription of pro-apoptotic genes at this time was also enhanced, suggesting that an apoptotic-like process was involved in DNA break production. Our results suggest that proliferating spermatogonia retain a memory of the radiation insult that is recognized at a later developmental stage and activates a process leading to DNA fragmentation. Environ. Mol. Mutagen. 53:429-439, 2012. V V C 2012 Wiley Periodicals, Inc.

show abstract

DNA-PK phosphorylates histone H2AX during apoptotic DNA fragmentation in mammalian cells

Cited by 181 publications

References 70 publications

H2AX phosphorylation marks gemcitabine-induced stalled replication forks and their collapse upon S-phase checkpoint abrogation

H2AX phosphorylation marks gemcitabine-induced stalled replication forks and their collapse upon S-phase checkpoint abrogation

HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia

Direct and delayed X‐ray‐induced DNA damage in male mouse germ cells

Contact Info

Product

Resources

About