Regulation of ultraviolet light-induced gene expression by gene size

McKay, Bruce C.; Stubbert, Lawton J.; Fowler, Casey C.; Smith, Jennifer; Cardamore, Robin A.; Spronck, Jennifer C.

doi:10.1073/pnas.0308181101

Cited by 93 publications

(97 citation statements)

References 47 publications

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“…It is possible that nuclear accumulation of p53 after UV-induced transcription blockage ensures a rapid and strong induction of target genes as transcription resumes after removal of transcription-blocking lesions by transcription-coupled repair. Only at high doses, UV light may stimulate p53-dependent apoptosis by preferentially inducing small apoptosis-promoting genes (34). Alternatively, the protective effect of nuclear accumulation of p53 after moderate doses of UV irradiation may be the result of the ability of p53 to enhance nucleotide excision repair by increasing DNA damage accessibility in chromatin (35).…”

Section: Discussionmentioning

confidence: 99%

RPA and ATR link transcriptional stress to p53

Derheimer

O’Hagan

Krueger

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

112

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The mechanisms by which DNA-damaging agents trigger the induction of the stress response protein p53 are poorly understood but may involve alterations of chromatin structure or blockage of either transcription or replication. Here we show that transcriptionblocking agents can induce phosphorylation of the Ser-15 site of p53 in a replication-independent manner. Furthermore, microinjection of anti-RNA polymerase II antibodies into the nuclei of cells showed that blockage of transcription is sufficient for p53 accumulation even in the absence of DNA damage. This induction of p53 occurs by two independent mechanisms. First, accumulation of p53 is linked to diminished nuclear export of mRNA; and second, inhibition specifically of elongating RNA polymerase II complexes results in the phosphorylation of the Ser-15 site of p53 in a replication protein A (RPA)-and ATM and Rad3-related (ATR)-dependent manner. We propose that this transcription-based stress response involving RPA, ATR, and p53 has evolved as a DNA damage-sensing mechanism to safeguard cells against DNA damage-induced mutagenesis.antibody microinjection ͉ DNA damage response ͉ RNA polymerase II ͉ nuclear export ͉ phosphorylation T he mechanisms by which DNA lesions are detected and how damage-response pathways are activated in cells are not well understood (1, 2). The stress-response kinases ataxia telangiectasia mutated (ATM) and ATM and Rad3-related (ATR) link DNA damage to p53 activation by phosphorylating the Ser-15 site of p53 (3-6). Although the ATM kinase is activated after exposure to ionizing radiation (7), the ATR kinase responds to agents that interfere with replication such as UV light and hydroxyurea (6). The tumor suppressor p53 is induced in response to a variety of different agents in all phases of the cell cycle (8,9). By acting as a transcription factor, p53 can induce the expression of gene products involved in DNA repair, cell cycle arrest, or apoptosis (10, 11). It can also regulate DNA repair and apoptosis by transcription-independent mechanisms (12). Under normal conditions, the p53 protein is rapidly targeted for nuclear export and degradation in a process regulated by the MDM2 protein (13). After cellular stress, the MDM2-mediated negative regulation of p53 is abrogated, and p53 proteins accumulate in the cell nucleus. This nuclear accumulation can be accomplished by (i) DNA damage-induced phosphorylation of p53 and MDM2, leading to the interference of the interaction between MDM2 and p53 (14); (ii) inactivation of proteasomes (15); or (iii) inhibition of the nuclear export machinery (13,16).DNA lesions that block RNA polymerase II induce the recruitment of transcription-coupled repair (TCR) and chromatin remodeling factors to recover RNA synthesis (17)(18)(19). Cells defective in TCR induce p53 and apoptosis at much lower doses than cells with proficient TCR, suggesting that lesions in the transcribed strand of active genes trigger these responses (9,(20)(21)(22). Although these studies have shown a correlation between blockage of ...

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Section: Discussionmentioning

confidence: 99%

RPA and ATR link transcriptional stress to p53

Derheimer

O’Hagan

Krueger

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

112

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“…16,17 While there are several potential mechanisms for the proapoptotic effect of overexpressed, pro-proliferative regulatory proteins, 18,19 a very credible possibility is represented by the difference in the gene sizes of pro-proliferative versus pro-apoptotic effector genes. McKay et al 20 in particular noticed the unusually small size of apoptosis genes, and later work by our group confirmed the relative size relationships between proproliferative and apoptosis-effector genes. 21 Furthermore, it has been demonstrated that pro-proliferative effector genes are much bigger "sinks" for pro-proliferative transcription factors, e.g., MYC.…”

Section: Introductionmentioning

confidence: 71%

TCGA: Increased oncoprotein coding region mutations correlate with a greater expression of apoptosis-effector genes and a positive outcome for stomach adenocarcinoma

Yavorski

Blanck

2016

Cell Cycle

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Oncogene mutations are primarily thought to facilitate uncontrolled cell growth. However, overexpression of oncoproteins likely leads to apoptosis in a feed forward mechanism, whereby a certain level of oncoprotein leads to the activation of pro-proliferation effector genes and higher levels lead to activation of pro-apoptotic effector genes. TCGA STAD barcodes having no oncoprotein coding region mutations represented reduced expression of the apoptosis-effector genes compared with barcodes with multiple oncoprotein coding region mutations. Furthermore, STAD barcodes in a "no-subsequent tumor" group, representing 224 samples, and in a "positive outcome" group, had more oncoprotein coding regions mutated, on average, than barcodes of the new tumor and negative outcome groups, respectively. BRAF, CTNNB1, KRAS and MTOR coding region mutations (as a group) had the strongest association with the no-subsequent tumor group. Tumor suppressor coding region mutations were also correlated with no-subsequent tumor. These results are consistent with an oncoprotein-mediated, feed-forward mechanism of apoptosis in patients. Importantly, the nosubsequent tumor group also had more overall mutations. This result leads to considerations of unhealthy cells or cells with more neo-antigens for immune rejection. However, a probabilistic aspect of mutagenesis is also consistent with more oncoprotein and tumor suppressor protein mutations, in cases of more overall mutations, and thus a higher likelihood of activation of feed forward apoptosis pathways.

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“…Even mildly cytotoxic doses of UV light induce sufficient DNA damage to block gene expression with (9,40,112,152,(155)(156)(157). The median size of protein coding genes is about 25 kb in length (158), so cells exposed to 10 J/m 2 of UV light sustain an average of 2.5 lesions per gene (109). Therefore, UV light leads to decreased nascent mRNA followed by recovery of mRNA synthesis as the DNA template is repaired (Fig.…”

Section: Uv Ddr the Transcription Paradox And Gene Sizementioning

confidence: 99%

“…In the absence of UV exposure, p53 can induce all size classes of p53 target genes (left panel). After cytotoxic doses of UV light (right panel), the expression of small genes p53-inducible genes increase more readily than average sized genes, while large p53 target genes cannot be induced efficiently (109). the recovery of mRNA synthesis (103,105,106,108) and inhibits 3¢ end processing after UV exposure through an interaction with the CstF/BARD1 complex (118).…”

Section: Introductionmentioning

confidence: 99%

“…With increasing doses of UV light, mRNA synthesis is inhibited more strongly and is less likely to recover within the indicated time frame. (B) Schematic representation of p53-induced gene expression in the presence and absence of pre-existing UV lesions (109). In the absence of UV exposure, p53 can induce all size classes of p53 target genes (left panel).…”

Section: Introductionmentioning

confidence: 99%

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Post-Transcriptional Regulation of DNA Damage-Responsive Gene Expression

McKay

2014

Antioxidants & Redox Signaling

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Significance: Production of proteins requires the synthesis, maturation, and export of mRNAs before their translation in the cytoplasm. Endogenous and exogenous sources of DNA damage pose a challenge to the coordinated regulation of gene expression, because the integrity of the DNA template can be compromised by DNA lesions. Cells recognize and respond to this DNA damage through a variety of DNA damage responses (DDRs). Failure to deal with DNA damage appropriately can lead to genomic instability and cancer. Recent Advances: The p53 tumor suppressor plays a dominant role in DDR-dependent changes in gene expression, but this transcription factor is not solely responsible for all changes. Recent evidence indicates that RNA metabolism is integral to DDRs as well. In particular, post-transcriptional processes are emerging as important contributors to these complex responses. Critical Issues: Transcriptional, post-transcriptional, and translational regulation of gene expression is subject to changes in response to DNA damage. How these processes are intertwined in the unfolding of DDR is not fully understood. Future Directions: Many complex regulatory responses combine to determine cell fate after DNA damage. Understanding how transcriptional, post-transcriptional, and translational processes interdigitate to create a web of regulatory interactions will be one of the key challenges to fully understand DDRs. Antioxid. Redox Signal. 20, 640-654.

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Regulation of ultraviolet light-induced gene expression by gene size

Cited by 93 publications

References 47 publications

RPA and ATR link transcriptional stress to p53

RPA and ATR link transcriptional stress to p53

TCGA: Increased oncoprotein coding region mutations correlate with a greater expression of apoptosis-effector genes and a positive outcome for stomach adenocarcinoma

Post-Transcriptional Regulation of DNA Damage-Responsive Gene Expression

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