A multifaceted role for ATM in genome maintenance

Pandita, Tej K.

doi:10.1017/s1462399403006318

Cited by 47 publications

(41 citation statements)

References 64 publications

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“…Such complexes have been reported to contain ATM-related proteins such as TRRAP, which is found in human Tip60 and PCAF complexes (3). ATM is implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination, cell cycle control, and telomere maintenance (50,52,53).…”

Section: Discussionmentioning

confidence: 99%

MOF and Histone H4 Acetylation at Lysine 16 Are Critical for DNA Damage Response and Double-Strand Break Repair

Sharma

Gupta

et al. 2010

Molecular and Cellular Biology

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284

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The human MOF gene encodes a protein that specifically acetylates histone H4 at lysine 16 (H4K16ac). Here we show that reduced levels of H4K16ac correlate with a defective DNA damage response (DDR) and double-strand break (DSB) repair to ionizing radiation (IR). The defect, however, is not due to altered expression of proteins involved in DDR. Abrogation of IR-induced DDR by MOF depletion is inhibited by blocking H4K16ac deacetylation. MOF was found to be associated with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a protein involved in nonhomologous end-joining (NHEJ) repair. ATM-dependent IR-induced phosphorylation of DNA-PKcs was also abrogated in MOF-depleted cells. Our data indicate that MOF depletion greatly decreased DNA double-strand break repair by both NHEJ and homologous recombination (HR). In addition, MOF activity was associated with general chromatin upon DNA damage and colocalized with the synaptonemal complex in male meiocytes. We propose that MOF, through H4K16ac (histone code), has a critical role at multiple stages in the cellular DNA damage response and DSB repair.In eukaryotes, specifically in mammals, the mechanisms by which the DNA damage response (DDR) components gain access to broken DNA in compacted chromatin remain a mystery. The DNA damage response occurs within the context of chromatin, and its structure is altered post-DNA double-strand break (DSB) induction. Major alterations include (i) chromatin remodeling via ATP-dependent activities and covalent histone modifications and (ii) incorporation of histone variants into nucleosomes. Chromatin structure creates a natural barrier to damaged DNA sites, which suggests that histone modifications will play a primary role in DDR by facilitating repair protein access to DNA breaks (43,58,87,88). While some experimental evidence indicates that preexisting histone modifications may play an important role in DDR, the precise role of chromatin status prior to DNA damage on DDR is yet to be clearly established. For instance, biochemical and cell biology studies indicate that repair proteins (53BP1, Schizosaccharomyces pombe Crb2 [SpCrb2], and Saccharomyces cerevisiae Rad9 [ScRad9]) require methylated Lys79 of histone H3 (H3-K79) (29) or methylated Lys20 of histone H4 (H4-K20) and/or CBP/p300-mediated acetylation of histone H3 on lysine 56 (9,15,29,66,93) for focus formation at DNA-damaged sites. These modifications are normally present on chromatin, and none has been reported to change in response to ionizing radiation (IR)-induced DNA damage. However, it is yet to be established whether preexisting acetylation of specific histone residues at the time of cellular exposure to IR plays any critical role in DDR. While recent studies demonstrate that in human cells, histone H3 acetylated at K9 (H3K9ac) and H3K56ac are rapidly and reversibly reduced in response to DNA damage, most histone acetylation modifications do not change appreciably after genotoxic stress (80).The amino-terminal tail of histone H4 is a well-described target fo...

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Section: Discussionmentioning

confidence: 99%

MOF and Histone H4 Acetylation at Lysine 16 Are Critical for DNA Damage Response and Double-Strand Break Repair

Sharma

Gupta

et al. 2010

Molecular and Cellular Biology

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284

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“…ATM (ataxia-telangiectasia-mutated protein) is crucial for the initiation of signaling pathways in mammalian cells following exposure to ionizing radiation (IR) and other DNA-damaging agents (36,46), and cells deficient in ATM function also have defective telomere chromatin (47). Bakkenist and Kastan (4) have suggested that chromatin structural perturbations induced by DNA double-strand breaks (DSBs) serve as a trigger for ATM activation.…”

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confidence: 99%

“…In mammalian cells, in response to DNA damage, ATM phosphorylates various proteins that control G 1 , S, and G 2 cell cycle arrest (13,36,46). We examined whether the inactivation of hMOF influences ATM-mediated IR-induced phosphorylation on Chk2 in 293 cells.…”

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confidence: 99%

Involvement of Human MOF in ATM Function

Gupta

Sharma

Young

et al. 2005

Molecular and Cellular Biology

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211

267

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We have determined that hMOF, the human ortholog of the Drosophila MOF gene (males absent on the first), encoding a protein with histone acetyltransferase activity, interacts with the ATM (ataxia-telangiectasiamutated) protein. Cellular exposure to ionizing radiation (IR) enhances hMOF-dependent acetylation of its target substrate, lysine 16 (K16) of histone H4 independently of ATM function. Blocking the IR-induced increase in acetylation of histone H4 at K16, either by the expression of a dominant negative mutant ⌬hMOF or by RNA interference-mediated hMOF knockdown, resulted in decreased ATM autophosphorylation, ATM kinase activity, and the phosphorylation of downstream effectors of ATM and DNA repair while increasing cell killing. In addition, decreased hMOF activity was associated with loss of the cell cycle checkpoint response to DNA double-strand breaks. The overexpression of wild-type hMOF yielded the opposite results, i.e., a modest increase in cell survival and enhanced DNA repair after IR exposure. These results suggest that hMOF influences the function of ATM.In eukaryotic cells, DNA damage activates signal transduction pathways that rapidly affect downstream processes such as gene transcription, cell cycle progression, and DNA replication (13,25). All of these processes involve alterations in chromatin structure. Posttranslational covalent modifications of histones have emerged as key regulatory events in DNA damage response. A widespread modification is acetylation catalyzed by histone acetyltransferases and reversed by deacetylases (3, 13, 50). Reversible acetylation of four lysines (K) at positions 5, 8, 12, and 16 in the amino-terminal tail of histone H4 occurs in vivo in all eukaryotes (3). The hyperacetylation of histone H4 could lead to the unfolding of the nucleosomal fiber (50), and the acetylation of histone H4 at K16 occurs on the hyperactive male X chromosome of Drosophila polytene chromosomes (51). Ikura et al. (19) noted that Tip60 (Tat-interacting protein), which acetylates histones H2A, H3, and H4, plays a role in DNA repair. More recently, Kusch et al. (28) demonstrated that the Drosophila Tip60 acetylates nucleosomal phosphoH2Av and exchanges it with an unmodified H2Av. Bird et al. (5) reported that the acetylation of histone H4 by Esa1 (essential SAS2-related acetyltransferase) is required for DNA repair in yeast and suggested that a similar modification may function in mammalian cells.ATM (ataxia-telangiectasia-mutated protein) is crucial for the initiation of signaling pathways in mammalian cells following exposure to ionizing radiation (IR) and other DNA-damaging agents (36, 46), and cells deficient in ATM function also have defective telomere chromatin (47). Bakkenist and Kastan (4) have suggested that chromatin structural perturbations induced by DNA double-strand breaks (DSBs) serve as a trigger for ATM activation. Recent studies indicate that the MRN (Mre11, Rad50, and Nbs1) complex as well as TRF2 either influences activation of ATM (9, 29, 52) or serves as a modulator/amp...

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“…Cells lacking functional ATM protein show increased sensitivity to ionizing radiation (IR) and other genotoxic events [40]. Our experiments showed that DZ1 indeed inhibited the ATM expression through the NF-κB pathway by decrease of the binding of NF-κB transcription factor to the ATM promoter (Figure 4), and increased radiosensitivity in LMP1-positive NPC cells.…”

Section: Impact Of Dz1 On Major Signal Pathways In Npc Cellsmentioning

confidence: 79%

A Therapeutic Approach to Nasopharyngeal Carcinomas by DNAzymes Targeting EBV LMP-1 Gene

Yang

et al. 2010

Molecules

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Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) has been known to have oncogenic properties during latent infection in nasopharyngeal carcinoma (NPC). Genetic manipulation of LMP1 expression may provide a novel strategy for the treatment of NPC. DNAzymes are synthetic, single-stranded DNA catalysts that can be engineered to bind and cleave the target mRNA of a disease-causing gene. By targeting the LMP1 mRNA, we successfully obtained a phosphorothioate-modified ''10-23'' DNAzyme namely DZ1, through screening a series of DNAzymes. DZ1 could significantly downregulate the expression of LMP1 in NPC cells, inhibit cell proliferation, metastasis, promote apoptosis and enhance radiosensitivity of NPC through interfering signal pathways which are abnormally activated by LMP1, including NF-κB, AP-1 and STAT3 signal pathways. Together, interfering LMP1 signaling pathway could be a promising strategy to target the malignant phenotypes of NPC.

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A multifaceted role for ATM in genome maintenance

Cited by 47 publications

References 64 publications

MOF and Histone H4 Acetylation at Lysine 16 Are Critical for DNA Damage Response and Double-Strand Break Repair

MOF and Histone H4 Acetylation at Lysine 16 Are Critical for DNA Damage Response and Double-Strand Break Repair

Involvement of Human MOF in ATM Function

A Therapeutic Approach to Nasopharyngeal Carcinomas by DNAzymes Targeting EBV LMP-1 Gene

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