Functional characterization of global genomic DNA repair and its implications for cancer

Hanawalt, Philip C.; Ford, James M.; Lloyd, Daniel R.

doi:10.1016/j.mrrev.2003.06.002

Cited by 122 publications

(69 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although speculative, the additional stress responsiveness for the DNA metabolism and repair genes in the primate lineage may reflect increased necessity for coordinated events or greater repair activity possibly during DNA replication. For example, the Ddb2 gene was shown to be nonresponsive to p53 in mice, and it was suggested that because rodents are nocturnal animals and also have a fur shield, there may be reduced selection for systems that tune the DNA damage responses to the UV component of sunlight (34,35). Consistent with our findings, an independent study that used comparative genomics to examine sequence conservation of Ͼ80 p53 REs between human and rodents also observed pronounced RE sequence divergence (36).…”

Section: Discussionsupporting

confidence: 84%

Functional evolution of the p53 regulatory network through its target response elements

Jegga

Inga²,

Menéndez

et al. 2008

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

View full text Add to dashboard Cite

Transcriptional network evolution is central to the development of complex biological systems. Networks can evolve through variation of master regulators and/or by changes in regulation of genes within networks. To gain insight into meaningful evolutionary differences in large networks, it is essential to address the functional consequences of sequence differences in response elements (REs) targeted by transcription factors. Using a combination of custom bioinformatics and multispecies alignment of promoter regions, we investigated the functional evolution of REs in terms of responsiveness to the sequence-specific transcription factor p53, a tumor suppressor and master regulator of stress responses. We identified REs orthologous to known p53 targets in human and rodent cells or alternatively REs related to the established p53 consensus. The orthologous REs were assigned p53 transactivation capabilities based on rules determined from model systems, and a functional heat map was developed to visually summarize conservation of sequence and relative level of responsiveness to p53 for 47 REs in 14 species. Individual REs exhibited marked differences in transactivation potentials and widespread evolutionary turnover. Functional differences were often not predicted from consensus sequence evaluations. Of the established human p53 REs analyzed, 91% had sequence conservation in at least one nonprimate species compared with 67.5% for functional conservation. Surprisingly, there was almost no conservation of functional REs for genes involved in DNA metabolism or repair between humans and rodents, suggesting important differences in p53 stress responses and cancer development. G ene expression largely depends on combinatorial interactions of transcription machineries with regulatory modules and is influenced by changes in chromatin structure (1-3). Sequence-specific transcription factors (TFs) can modulate expression of networks of target genes through dynamic interactions with unique cis-regulatory response elements (REs). Transcription network evolution is an important genetic component in phenotypic diversification between species. Transcriptional networks can transevolve through variation of master regulators or their targets or they can cis-evolve by changes in regulation of target genes. Cis-regulatory evolution, which can arise from point mutations, small deletions and additions, or large rearrangements of promoter regions, may be a major driver of species phenotypic differences (4). However, sequence-based analysis of phylogenetic conservation within regulatory regions has limitations because of an overall promoter organization that is less conserved compared with coding sequences. Although conservation of cis-regulatory sequence motifs may indicate preserved function within transcriptional networks, there are few comparative studies that address quantitatively the evolution of these regulatory interactions and examine the actual functionality of diverged REs in terms of ability to recruit TFs and mediate changes in...

show abstract

Section: Discussionsupporting

confidence: 84%

Functional evolution of the p53 regulatory network through its target response elements

Jegga

Inga²,

Menéndez

et al. 2008

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

View full text Add to dashboard Cite

show abstract

“…p53 is critical for maintaining genomic integrity after DNA damage inflicted by ␥ and UV irradiation or carcinogen exposure (Khanna and Jackson 2001;Hanawalt et al 2003). Cellular stress such as DNA damage or hypoxia causes up-regulation of p53, which then acts as a sequence-specific transcription factor driving expression of a range of genes such as p21, controlling G1/S cell cycle transition, or GADD45, involved in the G2/M DNA damage checkpoint.…”

Section: Tumor-suppressor Genes Frequently Inactivated In Lung Cancermentioning

confidence: 99%

Mouse models for human lung cancer

Meuwissen

Berns²

2005

Genes Dev.

271

243

View full text Add to dashboard Cite

In recent years several new mouse models for lung cancer have been described. These include models for both non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Tumorigenesis in these conditional mouse tumor models can be initiated in adult mice through Cre-recombinase-induced activation of oncogenic mutations in a subset of the cells. They present a marked improvement over mouse models that depend on carcinogen induction of tumors. These models permit us to study the consecutive steps involved in initiation and progression and allow us to address questions like the cell of origin, and the role of cancer stem cells in the maintenance of these tumors. They now need to be validated as suitable preclinical models for intervention studies in which questions with respect to therapy response and resistance can be addressed.During the last decades lung cancer has become the leading cause of cancer deaths in the world, accounting for even more solid tumor deaths than breast, pancreatic, prostate, and colorectal combined (Landis et al. 1999). More then 170,000 new cases are being diagnosed each year in the United States alone, of whom ∼160,000 will eventually die, representing 28% of all cancer deaths (Jemal et al. 2004). Worldwide more than a million deaths are due to lung cancer. Tobacco smoking is the major causal agent, being responsible for ∼85% of the lung cancer incidence. Other respiratory exposure to occupational or environmental carcinogens, such as asbestos or radon, and yet unknown genetic factors contribute to the remaining 15% . Although smoking cessation before the age of 30 does substantially reduce the risk of lung cancer, this is significantly less for those who stop smoking at 50 or 60 yr (Peto et al. 2000;Doll et al. 2004). Interestingly, nearly 50% of all first diagnosed lung cancers in the United States are from people who stopped smoking at least 5 or more years ago (Peto and Lopez 2001). This indicates that extensive damage to the respiratory tract can persist over many years. Indeed, recent studies (Mao 2002;Pfeifer et al. 2002;Wistuba et al. 2002) showed the presence of multiple genetic lesions, often manifested in clonal patches of cells in respiratory epithelium of current and former smokers.Lung cancer can be divided into two major histopathological groups: non-small-cell lung cancer (NSCLC) (Van Zandwijk et al. 1995) SCLC and NSCLC show major differences in histopathologic characteristics that can be explained by the distinct patterns of genetic lesions found in both tumor classes . Responsiveness to treatment with chemotherapy and/or radiation also differs significantly between NSCLC and SCLC and has a dramatic effect on clinical treatment outcome. The overall 5-yr survival rate for lung cancer is ∼14% (Travis et al. 1995); for SCLC alone it is even worse, ∼5% (Worden and Kalemkerian 2000).Spontaneous lung tumors in mice are similar in morphology, histopathology, and molecular characteristics to human adenocarcinomas. Mouse models for lung cancer can thus serve as a valua...

show abstract

“…NER is a complex process involving the concerted action of ~30 proteins that recognize the lesion, remove a short segment of the damaged strand, replace it using the complementary DNA strand as template for repair replication, and seal the "repair patch" by ligation to the contiguous parental strand [Hanawalt et al, 2003]. NER targets primarily bulky helixdistorting lesions, and there are two NER repair subpathways: global-genome repair (GG-NER) and targeted repair, which is also called transcription-coupled repair (TCR).…”

Section: Session 9: Challenges In Linking Human Exposure To Increasedmentioning

confidence: 99%

Assessing human germ‐cell mutagenesis in the Postgenome Era: A celebration of the legacy of William Lawson (Bill) Russell

Wyrobek

Mulvihill

Wassom

et al. 2007

Environ and Mol Mutagen

View full text Add to dashboard Cite

Birth defects, de novo genetic diseases, and chromosomal abnormality syndromes occur in ~5% of all live births, and affected children suffer from a broad range of lifelong health consequences. Despite the social and medical impact of these defects, and the 8 decades of research in animal systems that have identified numerous germ-cell mutagens, no human germ-cell mutagen has been confirmed to date. There is now a growing consensus that the inability to detect human germ-cell mutagens is due to technological limitations in the detection of random mutations rather than biological differences between animal and human susceptibility. A multidisciplinary workshop responding to this challenge convened at The Jackson Laboratory in Bar Harbor, Maine. The purpose of the workshop was to assess the applicability of an emerging repertoire of genomic technologies to studies of human germ-cell mutagenesis. Workshop participants recommended large-scale human germ-cell mutation studies be conducted using samples from donors with high-dose exposures, such as cancer survivors. Within this high-risk cohort, parents and children could be evaluated for heritable changes in (a) DNA sequence and chromosomal structure, (b) repeat sequences and minisatellites, and (c) global gene expression profiles and pathways. Participants also advocated the establishment of a bio-bank of human tissue samples from donors with well-characterized exposure, including medical and reproductive histories. This mutational resource could support large-scale, multipleendpoint studies. Additional studies could involve the examination of transgenerational effects NIH Public AccessAuthor Manuscript Environ Mol Mutagen. Author manuscript; available in PMC 2007 November 8. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript associated with changes in imprinting and methylation patterns, nucleotide repeats, and mitochondrial DNA mutations. The further development of animal models and the integration of these with human studies are necessary to provide molecular insights into the mechanisms of germcell mutations and to identify prevention strategies. Furthermore, scientific specialty groups should be convened to review and prioritize the evidence for germ-cell mutagenicity from common environmental, occupational, medical, and lifestyle exposures. Workshop attendees agreed on the need for a full-scale assault to address key fundamental questions in human germ-cell environmental mutagenesis. These include, but are not limited to, the following: Do human germ-cell mutagens exist? What are the risks to future generations? Are some parents at higher risk than others for acquiring and transmitting germ-cell mutations? Obtaining answers to these, and other critical questions, will require strong support from relevant funding agencies, in addition to the engagement of scientists outside the fields of genomics and germ-cell mutagenesis.

show abstract

Functional characterization of global genomic DNA repair and its implications for cancer

Cited by 122 publications

References 52 publications

Functional evolution of the p53 regulatory network through its target response elements

Functional evolution of the p53 regulatory network through its target response elements

Mouse models for human lung cancer

Assessing human germ‐cell mutagenesis in the Postgenome Era: A celebration of the legacy of William Lawson (Bill) Russell

Contact Info

Product

Resources

About