Cell cycle checkpoint defects contribute to genomic instability in PTEN deficient cells independent of DNA DSB repair

Gupta, A.; Yang, Qin; Pandita, Raj K.; Hunt, Clayton R.; Tang, Xiang; Misri, Sandeep; Zeng, Sicong; Pagan, Julia K.; Jeffery, Jessie; Puc, Janusz; Kumar, Rakesh; Feng, Zhihui; Powell, Simon N.; Bhat, Audesh; Yaguchi, Tomoko; Wadhwa, Renu; Kaul, Sunil C.; Parsons, Ramon; Khanna, Kum Kum; Pandita, Tej K.

doi:10.4161/cc.8.14.8947

Cited by 112 publications

(122 citation statements)

References 59 publications

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“…Although the 5Ј-blocked substrate showed a large decrease in activity ( Fig. 2A, lanes 14 -16), the 3Ј-blocked substrate showed only marginal inhibition (lanes [17][18][19], suggesting that hEXO5 is primarily a 5Ј-exonuclease, but it may also have 3Ј-exonuclease activity (Fig. 2B).…”

Section: Resultsmentioning

confidence: 99%

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Human Exonuclease 5 Is a Novel Sliding Exonuclease Required for Genome Stability

Sparks

Kumar

Singh

et al. 2012

Journal of Biological Chemistry

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Background: Deoxyribonucleases are key DNA metabolic enzymes, but their functions remain ill defined. Results: Human EXO5 is a novel bidirectional single strand-specific sliding exonuclease; however, RPA enforces a 5Ј-directionality of nuclease activity. Conclusion: hEXO5 functions in nuclear genome maintenance and interstrand cross-link repair. Significance: Nucleases are important in directing pathway choices at DNA damage and replication blocks.

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Section: Resultsmentioning

confidence: 99%

“…Cells were fixed in 2% paraformaldehyde for 15 min, washed in 1ϫ PBS, permeabilized for 5 min on ice in 0.2% Triton X-100, and blocked in PBS with 1% bovine serum albumin. The procedure used for immunostaining is the same as that described previously (17)(18)(19).…”

Section: Methodsmentioning

confidence: 99%

Human Exonuclease 5 Is a Novel Sliding Exonuclease Required for Genome Stability

Sparks

Kumar

Singh

et al. 2012

Journal of Biological Chemistry

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“…Cell culture in chamber slides, fixation, and immunostaining were done as previously described (1,28,59). Fluorescent images of foci were captured as described previously (26). Sections through nuclei were captured, and the images were obtained by projection of the individual sections as recently described (48).…”

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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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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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“…These mutations leave the phosphatase activity intact (22). Inhibition of PTEN activity leads to centromere breakage and chromosome instability (23). Thus, PTEN has diverse activities.…”

Section: Pten Mutations In Human Cancermentioning

confidence: 99%

Gene alterations in the PI3K/PTEN/AKT pathway as a mechanism of drug-resistance (Review)

Hafsi

Pezzino²,

Candido³

et al. 2011

Int J Oncol

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Abstract. The most common therapeutic approach for many cancers is chemotherapy. However, many patients relapse after treatment due to the development of chemoresistance. Recently, targeted therapies represent novel approaches to destroy cancer cells. The PI3K/PTEN/AKT pathway is a key signaling pathway involved in the regulation of cell growth. Dysregulated signaling of this pathway may be associated with activating mutations of PI3K-related genes. Analyses of these mutations reveal that they increase the PI3K signal, stimulate downstream Akt signaling, promote growth factor-independent growth and increase cell invasion and metastasis. In this review, we summarize the PI3K/PTEN/AKT pathway genetic alterations in cancer and their potential clinical applications. IntroductionPhosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that phosphorylate phoshoinositides at the D-3 position of the inositol ring generating second messengers that govern cellular activities and promote various biological properties including proliferation, survival, motility and morphology changes. Members of the PI3K family are grouped into three classes according to sequence homology, substrate preference and tissue distribution (1). In terms of regulating cell division and tumorigenesis, the most important PI3K proteins are those that belong to class IA, the catalytic subunit p110α and its associated regulatory subunit p85. In quiescent cells, the regulatory subunit p85 maintains the p110α catalytic subunit in a lowactivity state. Upon growth factor stimulation, the SH2 domain [Rous-sarcoma (src) oncogene homology-2 domain] of the p85 subunit binds to phosphorylated tyrosine in receptor tyrosine kinases or their substrate adaptor proteins. This binding relieves the inhibition of p110α subunit and mediates recruitment of this subunit to the plasma membrane (2). Activation of p110α leads to the production of phosphatidylinositol 3,4,5-triphosphate (PIP3), which recruits adaptor and effector proteins containing a pleckstrin homology domain (PH domain) to cellular membranes including the protein kinase B (PKB/Akt), phosphoinositide-dependent kinase 1 (PDK-1) (3). Once at the membrane PKB/Akt is phosphorylated at Thr308 and Ser473 by PDK1 and the mTORC2 complex, respectively. Once activated PKB/Akt phosphorylates and actives target proteins involved in many different cellular functions, which span cell cycle progression, cell survival, metabolism, ribosome biogenesis, protein translation, RNA transcription and cell motility (4,5

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Cell cycle checkpoint defects contribute to genomic instability in PTEN deficient cells independent of DNA DSB repair

Cited by 112 publications

References 59 publications

Human Exonuclease 5 Is a Novel Sliding Exonuclease Required for Genome Stability

Human Exonuclease 5 Is a Novel Sliding Exonuclease Required for Genome Stability

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

Gene alterations in the PI3K/PTEN/AKT pathway as a mechanism of drug-resistance (Review)

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