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PubMed1997

Breast cancer metastasis-associated genes: prognostic significance and therapeutic implications.

The metastatic spread of breast cancer accounts for most of its morbidity and mortality; therefore, identifying the genes and gene products involved in breast cancer metastasis formation should be useful for better diagnosis, prognosis, treatment, and follow-up of patients with metastatic breast cancer. Unfortunately, little is known about these genes or the functions of their encoded products. Abnormalities in at least three broad gene categories (oncogenes, regulatory genes or effector genes, and tumor-suppressor genes) have been shown to contribute to the origin and/or progression of breast neoplasias. Such abnormalities are mainly manifested by quantitative changes in gene expression, resulting in loss of normal cellular regulation and enhanced cellular diversification. In addition, qualitative genetic alterations, such as gene amplifications and mutations, may also be involved in breast cancer progression. The role(s) of different breast cancer metastasis-associated genes, if known, in the complex multistep process of invasion and metastasis is discussed along with studies that have identified new molecular probe(s) that may be useful in predicting metastasis formation and outcome in breast cancer and for selecting candidates for adjuvant therapy. Understanding the genetic and thus molecular basis of metastasis formation should also provide important insights on the development of new therapeutic approaches for treatment of metastatic breast cancers based on gene targeting and repair of genetic defects that control metastatic properties.

Breast Neoplasms↗

PubMed1996

Redox regulation of transcriptional activators.

Transcription factors/activators are a group of proteins that bind to specific consensus sequences (cis elements) in the promoter regions of downstream target/effector genes and transactivate or repress effector gene expression. The up- or downregulation of effector genes will ultimately lead to many biological changes such as proliferation, growth suppression, differentiation, or senescence. Transcription factors are subject to transcriptional and posttranslational regulation. This review will focus on the redox (reduction/oxidation) regulation of transcription factors/activators with emphasis on p53, AP-1, and NF-kappa B. The redox regulation of transcriptional activators occurs through highly conserved cysteine residues in the DNA binding domains of these proteins. In vitro studies have shown that reducing environments increase, while oxidizing conditions inhibit sequence-specific DNA binding of these transcriptional activators. When intact cells have been used for study, a more complex regulation has been observed. Reduction/oxidation can either up- or downregulate DNA binding and/or transactivation activities in transcriptional activator-dependent as well as cell type-dependent manners. In general, reductants decrease p53 and NF-kappa B activities but dramatically activate AP-1 activity. Oxidants, on the other hand, greatly activate NF-kappa B activity. Furthermore, redox-induced biochemical alterations sometimes lead to change in the biological functions of these proteins. Therefore, differential regulation of these transcriptional activators, which in turn, regulate many target/effector genes, may provide an additional mechanism by which small antioxidant molecules play protective roles in anticancer and antiaging processes. Better understanding of the mechanism of redox regulation, particularly in vivo, will have an important impact on drug discovery for chemoprevention and therapy of human disease such as cancer.

Animals↗

PubMed2004

Reflections on an unsolved problem of biology: the evolution of senescence and death.

The evolutionary theory of senescence is based largely on principles first outlined by Williams in 1957, and consists of two relatively independent parts. The first part builds on ideas first put forward by Medawar, Haldane and others, to explain how something as negative as senescence could have been positively selected in evolution, particularly since most animals in the wild do not reach an age where senescence is expressed. Williams proposed that the genes responsible for the negative effects of senecence (senescence effector genes) were fixed in evolution by a process he called antagonistic pleiotropy, wherein a subset of genes selected because they confer a reproductive advantage early in life may have harmful effects in the post-reproductive period; negative selection against these harmful effects fails because, as pointed out by Medawar, the force of natural selection declines with age. The evolutionary history of senescence-causing genes is seen as a nondirected accumulation of genes selected on a basis independent of senescence per se. In the second portion of his paper, Williams made a series of predictions about how the age of organisms at reproductive maturity, fecundity, lifespan and the timing of the onset of senescence would all interact in the life history of a species. These latter predictions, which do not depend at all on details of the mechanisms of selection of senescence effector genes, have been validated by numerous experiments over the past several decades. On the other hand, it has become increasingly evident that the senescence effector genes did not, as would be predicted by antagonistic pleiotropy, accumulate in a random, non-directed fashion in various species over evolutionary time. Rather, everything we know about these genes suggests they were present in eukaryotic founder cells shortly after, or even congruent with, the emergence of eukaryotes from their prokaryotic ancestors, and have been stringently conserved ever since. Complicated explanations of how so-called "death genes" may have evolved in eukaryotes are thus not required. It is suggested that the evolutionary theory of senescence should be focused on those evolutionary principles that have been validated experimentally, and that the notion of antagonistic pleiotropy--which cannot be experimentally validated--be dropped from our thinking about the evolution of senescence.

Aging↗

PubMed2003

Bidirectional expression units enable streptogramin-adjustable gene expression in mammalian cells.

Serious initiatives in gene therapy and tissue engineering require a sophisticated molecular toolbox combining DNA transfer technologies, human-compatible transcription control systems, as well as compact and robust expression configurations. We have designed several versatile bidirectional expression cassettes that enable coadjustable expression of two desired transgenes in response to clinically licensed antibiotics of the streptogramin class (pristinamycin, Pyostacin, Synercid). The bidirectional expression modules consist of a central operator (PIR) that is specific for the pristinamycin-dependent transactivator (PIT). Streptogramin-adjustable binding of PIT to PIR transactivates two divergently oriented promoters and initiates transcription of the desired transgenes. The bidirectional expression module can be equipped with different minimal promoters and configured for expression of (1) two functional effector genes, (2) one effector gene and a reporter gene, (3) PIT and an effector gene to form a highly compact one-vector expression arrangement. We have validated the streptogramin-adjustable bidirectional expression technology in different basic and autoregulated expression configurations in a variety of mammalian and human cell lines.

Alkaline Phosphatase↗

PubMed2026

Genome-wide association and multi-omics functional screens reveal the genetic architecture of foveal development.

Foveal hypoplasia causes visual impairment across congenital eye disorders, yet the genetic programmes governing foveal development remain poorly characterised and no tractable model exists for foveal disease. In the first genome-wide association study of foveal hypoplasia, we identified 42 sentinel variants mapping to 54 effector genes supported by ≥ 2 criteria from a variant-to-gene framework incorporating developmental multi-omics. Disruption of six effector genes using mutant lines and CRISPR knockouts in the zebrafish high acuity zone recapitulates structural, functional, and ultrastructural hallmarks of foveal hypoplasia, establishing the first vertebrate disease model. Integration with human foetal single-cell and spatial transcriptomics reveals two temporal waves of effector gene expression and identifies Müller glia as critical mediators of foveal patterning. Phenome-wide analyses reveal foveal variants are pleiotropic with refractive, lenticular, and metabolic traits, connecting foveal development to anterior segment and systemic disease biology. These findings should inform mechanistic studies of macular disease.

Journal Article↗

PubMed2006

Os8N3 is a host disease-susceptibility gene for bacterial blight of rice.

Many bacterial diseases of plants depend on the interaction of type III effector genes of the pathogen and disease-susceptibility genes of the host. The host susceptibility genes are largely unknown. Here, we show that expression of the rice gene Os8N3, a member of the MtN3 gene family from plants and animals, is elevated upon infection by Xanthomonas oryzae pv. oryzae strain PXO99(A) and depends on the type III effector gene pthXo1. Os8N3 resides near xa13, and PXO99(A) failed to induce Os8N3 in rice lines with xa13. Silencing of Os8N3 by inhibitory RNA produced plants that were resistant to infection by strain PXO99(A) yet remained susceptible to other strains of the pathogen. The effector gene avrXa7 from strain PXO86 enabled PXO99(A) compatibility on either xa13- or Os8N3-silenced plants. The findings indicate that Os8N3 is a host susceptibility gene for bacterial blight targeted by the type III effector PthXo1. The results support the hypothesis that X. oryzae pv. oryzae commandeers the regulation of otherwise developmentally regulated host genes to induce a state of disease susceptibility. Furthermore, the results support a model in which the pathogen induces disease susceptibility in a gene-for-gene manner.

Amino Acid Sequence↗

PubMed2002

Bee venom phospholipase inhibits malaria parasite development in transgenic mosquitoes.

Malaria kills millions of people every year, and new control measures are urgently needed. The recent demonstration that (effector) genes can be introduced into the mosquito germ line to diminish their ability to transmit the malaria parasite offers new hope toward the fight of the disease (Ito, J., Ghosh, A., Moreira, L. A., Wimmer, E. A. & Jacobs-Lorena, M. (2002) Nature, 417, 452-455). Because of the high selection pressure that an effector gene imposes on the parasite population, development of resistant strains is likely to occur. In search of additional antiparasitic effector genes, we have generated transgenic Anopheles stephensi mosquitoes that express the bee venom phospholipase A2 (PLA2) gene from the gut-specific and blood-inducible Anopheles gambiae carboxypeptidase (AgCP) promoter. Northern blot analysis indicated that the PLA2 mRNA is specifically expressed in the guts of transgenic mosquitoes with peak expression at approximately 4 h after blood ingestion. Western blot and immunofluorescence analyses detected PLA2 protein in the midgut epithelia of transgenic mosquitoes from 8 to 24 h after a blood meal. Importantly, transgene expression reduced Plasmodium berghei oocyst formation by 87% on average and greatly impaired transmission of the parasite to naive mice. The results indicate that PLA2 may be used as an additional effector gene to block the development of the malaria parasite in mosquitoes.

Animals↗

PubMed2005

AUXIN RESPONSE FACTOR7 restores the expression of auxin-responsive genes in mutant Arabidopsis leaf mesophyll protoplasts.

AUXIN RESPONSE FACTOR7 (ARF7) is one of five ARF transcriptional activators in Arabidopsis thaliana that is proposed to regulate auxin-responsive expression of genes containing TGTCTC auxin response elements in their promoters. An Arabidopsis mutant (nonphototropic hypocotyl4-1 [nph4-1]) that is a null for ARF7 showed strongly reduced expression of integrated auxin-responsive reporter genes and natural genes that were monitored in Arabidopsis leaf mesophyll protoplasts. Expression of the reporter and natural genes was restored in an auxin-dependent manner when protoplasts were transfected with a 35S:ARF7 effector gene, encoding a full-length ARF7 protein. Transfection of effector genes encoding other ARF activators restored auxin-responsive gene expression to varying degrees, but less than that observed with the ARF7 effector gene. Arabidopsis lines that were null for ARF6, ARF8, or ARF19 were not defective in expression of the reporter and natural auxin response genes assayed in mesophyll protoplasts, suggesting that ARF7 plays a major role in regulating expression of a subset of auxin response genes in leaf mesophyll cells. Auxin-responsive gene expression was induced in wild-type protoplasts and restored in nph4-1 protoplasts only with auxin and not with other hormones, including brassinolide. In the presence of auxin, however, brassinolide modestly enhanced auxin-responsive gene expression.

Arabidopsis↗

PubMed1996

Characterization of the GADD45 response to ionizing radiation in WI-L2-NS cells, a p53 mutant cell line.

We have previously reported that WI-L2-NS, a human lymphoblastoid cell line, has very high basal levels of GADD45 mRNA and protein in spite of a p53 mutation at amino acid 237. Regardless of the amount of Gadd45 in this cell line, no growth suppression activity was detected. We report here that in WI-L2-NS, the mutated p53 protein adopts predominantly a wild type (wt) conformation and binds to the p53 binding site in the GADD45 third intron. In this cell line, the already high levels of mutated p53 protein can be induced further by ionizing radiation (IR) but the response of the p53 downstream effector genes is altered. Induction of GADD45 and CIP1/WAF1 is reduced compared to p53 wt cell lines but is still substantially higher than the average fold induction obtained from 39 p53 mutant cell lines. Induction of the MDM2 gene was not detected in WI-L2-NS following IR. The induction pattern of the three p53 effector genes by the alkylating agent methylmethane sulfonate (MMS) was also attenuated in WI-L2-NS cells. In TK6 cells, a WI-L2-NS sister cell line having a p53 wt genotype, the induction of the p53 downstream effectors is normal, i.e. induced, both at the protein and the mRNA levels. These results indicate that the DNA binding activity of the mutated p53 protein in WI-L2-NS might be responsible, at least in part, for the high basal levels of GADD45 but can not mediate the full induction of the p53 downstream effector genes. The reason(s) for the inability of Gadd45 to suppress growth in this cell line remains however unknown.

Alkylating Agents↗

PubMed2026

Cross-species variant-to-function analyses implicate MEIS1 in conferring sleep abnormalities and impaired cerebellar development.

Genome-wide association studies (GWAS) have identified numerous loci for insomnia, yet functional validation of effector genes remains limited because most risk variants lie in noncoding regions, and the true causal gene is not known. Here, we use prior human cell-based variant-to-gene mapping to nominate six insomnia effector genes and test them in zebrafish, a tractable diurnal vertebrate model well suited for sleep phenotyping. Our CRISPR-based behavioral screening identifies the MEIS1 ortholog, meis1b, as a regulator of sleep maintenance, with crispants displaying impaired nighttime-specific sleep maintenance and increased sleep latency. Comparative chromatin analyses reveal conserved regulatory architecture spanning the human insomnia-associated locus and selectively implicate meis1b, whereas the duplicated ohnolog meis1a was dispensable. Developmental profiling further shows that meis1b is expressed in cerebellar granule progenitors, paralleling human MEIS1 expression, and that its disruption impairs cerebellar development. Together, these findings establish zebrafish as an efficient vertebrate platform for functional interrogation of GWAS candidates and support an evolutionarily conserved cerebellar role for MEIS1 in sleep maintenance.

Animals↗

PubMed2002

Specific induction of gadd45 in human melanocytes and melanoma cells after UVB irradiation.

The purpose of our study was to analyze the p53-mediated response of human melanocytes and human melanoma cells to UVB (natural environmental carcinogen) or UVC irradiation (experimental carcinogen). A semi-quantitative RT-PCR method was developed to allow the analysis of the expression of 5 p53 effector genes (p21(WAF1), mdm2, cyclin G1, gadd45, bax) at the same time with a small amount of RNA (1 microg). In human melanocytic cells, the p53 downstream genes were found to be differentially activated after UVB and UVC irradiation. After UVB irradiation, p53 protein accumulation was sustained up to 48 hr that was not the case after UVC irradiation. Among the p53 effector genes tested, gadd45 was the only 1 to show a strong and specific induction after UVB irradiation. With high UVB doses, gadd45 was also the only gene to be transcribed. By contrast, after UVC irradiation, all the p53 effector genes tested were transcriptionally induced. Experiments conducted with fibroblasts and keratinocytes didn't show such a striking activation of gadd45 after UVB irradiation. These results point out the potential role of gadd45 in response to UVB irradiation in human melanocytes and the different p53-mediated responses to different carcinogens.

Cells, Cultured↗

PubMed2026

Genetic and epigenetic underpinnings of biological aging: a multi-omics study integrating Mendelian randomization, spatial transcriptomics, and drug target discovery.

Inflammaging represents a hallmark of biological aging, yet the causal inflammatory mediators driving multi-dimensional epigenetic aging and their effector genes remain poorly characterized at the genetic level. We developed a four-tier analytical framework integrating causal screening, multi-omics effector gene mapping, spatial transcriptomics, and drug target evaluation. Two-sample Mendelian randomization (MR) of 91 circulating inflammatory proteins against six aging phenotypes identified IL-12B, IFNG, and IL-2 as the most robust pro-aging mediators with consistent effects across independent outcomes. Using multi-omics summary-based MR (SMR) as the core analytical engine, we integrated four-layer whole-blood molecular QTL resources eQTL (eQTLGen, n = 31,684), sQTL (GTEx, n = 755), pQTL (INTERVAL + SCALLOP, n = 34,232), and mQTL (McRae et al., n = 1,980) - with GWAS summary statistics for four epigenetic age acceleration measures. At a stringent threshold (P_SMR < 1×10⁻¹²), seven high-confidence effector genes were identified: NHLRC1, TPMT, SELP, and RIPPLY3 for IEAA; ZNF373A and PLDN for HannumAA; and EDARADD for PhenoAA. The chromosome 6p21 NHLRC1-TPMT locus, overwhelmingly driven by methylation QTL signals (-log₁₀P = 26.06), emerged as the dominant genetic node of epigenetic aging. Spatial projection via gsMap onto a mouse E16.5 embryo atlas (121,767 cells) revealed preferential enrichment in smooth muscle and lung, with EDARADD showing marked specificity in mucosal epithelium. Cross-database drug target mining classified TPMT and SELP as repurposable known targets and NHLRC1 as a high-priority novel druggable candidate. This study provides multi-omics convergent causal evidence for inflammation-driven epigenetic aging and delivers genetically anchored targets for precision anti-aging intervention.

Aging↗

PubMed2006

Cage trials using an endogenous meiotic drive gene in the mosquito Aedes aegypti to promote population replacement.

Control of arthropod-borne diseases based on population replacement with genetically modified non-competent vectors has been proposed as a promising alternative to conventional control strategies. Due to likely fitness costs associated with vectors manipulated to carry anti-pathogen effector genes, the effector genes will need to be coupled with a strong drive system to rapidly sweep them into natural populations. Endogenous meiotic drive systems have strong and stable population replacement potential, and have previously been reported in two mosquito species: Aedes aegypti and Culex pipiens. To investigate the influence of an endogenous meiotic drive gene on Ae. aegypti population dynamics, we established three experimental population types that were initiated with 100%, 10%, and 1% male mosquitoes carrying a strong meiotic driver (T37 strain) and 100% sensitive females (RED strain), respectively. Among the 100% and 10% populations, early generations were highly male biased, which reflected the effects of the meiotic driver, and remained more than 60% male by the F(15). A genetic marker tightly linked with the meiotic driver on chromosome 1 showed strong selection for the T37 strain-specific allele. Similar but reduced effects of the meiotic driver were also observed in the 1% populations. These results suggest that release of Ae. aegypti males carrying a strong meiotic driver into drive sensitive populations can be an effective tool for population replacement, and provide a foundation for additional studies including both experimental populations and simulations by mathematical modeling.

Aedes↗

PubMed2005

Integration of oxygen signaling at the consensus HRE.

The hypoxia-inducible factor 1 (HIF-1) was initially identified as a transcription factor that regulated erythropoietin gene expression in response to a decrease in oxygen availability in kidney tissue. Subsequently, a family of oxygen-dependent protein hydroxylases was found to regulate the abundance and activity of three oxygen-sensitive HIFalpha subunits, which, as part of the HIF heterodimer, regulated the transcription of at least 70 different effector genes. In addition to responding to a decrease in tissue oxygenation, HIF is proactively induced, even under normoxic conditions, in response to stimuli that lead to cell growth, ultimately leading to higher oxygen consumption. The growing cell thus profits from an anticipatory increase in HIF-dependent target gene expression. Growth stimuli-activated signaling pathways that influence the abundance and activity of HIFs include pathways in which kinases are activated and pathways in which reactive oxygen species are liberated. These pathways signal to the HIF protein hydroxylases, as well as to HIF itself, by means of covalent or redox modifications and protein-protein interactions. The final point of integration of all of these pathways is the hypoxia-response element (HRE) of effector genes. Here, we provide comprehensive compilations of the known growth stimuli that promote increases in HIF abundance, of protein-protein interactions involving HIF, and of the known HIF effector genes. The consensus HRE derived from a comparison of the HREs of these HIF effectors will be useful for identification of novel HIF target genes, design of oxygen-regulated gene therapy, and prediction of effects of future drugs targeting the HIF system.

Animals↗

PubMed2006

Immune activation at effector and gene expression levels after measles vaccination in healthy individuals: a pilot study.

Cellular immunity to measles vaccination is not fully understood at the effector response and gene expression levels. We enrolled 15 healthy individuals (15-25 years old) previously vaccinated with two doses of measles-mumps-rubella-II vaccine to characterize their cellular immunity. We detected a spectrum of lymphoproliferative response (median stimulation indices of 3.4), low precursor frequencies of interferon-gamma (median 0.11%) and interleukin-4 (median 0.05%) by Elispot, and cosecretion of Th1 and Th2 cytokines after measles virus stimulation. Further, global gene expression was examined in five subjects from this cohort after vaccination with an additional dose of measles vaccine (Attenuax, Merck) to identify the genes involved in measles immunity. Linear mixed effect models were used to identify genes significantly up or downregulated in vivo between baseline and Days 7 and 14 after measles vaccination. Measles vaccination induced upregulation of a set of 80 genes, which play a role in measles immunity, signal transduction, apoptosis, cell proliferation, and metabolic pathways. Among the 34 genes that were downregulated, only interferon-alpha is known to have a direct role in measles immunity. This study suggests that measles vaccination leads to activation of multiple cellular mechanisms that can override the immunosuppressant effects of the measles virus and induce immunity.

Adolescent↗

PubMed2006

Hox control of morphogen mobility and organ development through regulation of glypican expression.

Animal bodies are composed of structures that vary in size and shape within and between species. Selector genes generate these differences by altering the expression of effector genes whose identities are largely unknown. Prime candidates for such effector genes are components of morphogen signaling pathways, which control growth and patterning during development. Here we show that in Drosophila the Hox selector gene Ultrabithorax (Ubx) modulates morphogen signaling in the haltere through transcriptional regulation of the glypican dally. Ubx, in combination with the posterior selector gene engrailed (en), represses dally expression in the posterior (P) compartment of the haltere. Compared with the serially homologous wing, where Ubx is not expressed, low levels of posterior dally in the haltere contribute to a reduced P compartment size and an overall smaller appendage size. We also show that one molecular consequence of dally repression in the posterior haltere is to reduce Dpp diffusion into and through the P compartment. Our results suggest that Dpp mobility is biased towards cells with higher levels of Dally and that selector genes modulate organ development by regulating glypican levels.

Animals↗

PubMed2026

Genetic Determinants of Pulmonary Artery Size in over 50,000 Subjects with and without COPD.

RATIONALE: Pulmonary artery (PA) enlargement is a non-invasive imaging biomarker associated with pulmonary hypertension and mortality in COPD; however, its genetic determinants remain incompletely understood. OBJECTIVES: To characterize the genetic architecture of PA size across COPD-enriched and population-based cohorts. METHODS: We performed genome-wide association analyses of PA diameter using whole-genome sequencing in COPDGene (n=9,418) and ECLIPSE (n=1,859), and imputed-genotype data from the UK Biobank (n=37,073). We replicated lead variants in the Framingham Heart Study (FHS; n=3,289), incorporated all four studies into a joint meta-analysis, and identified independent signals through conditional analyses. Candidate effector genes were prioritized using coding variant annotation, colocalization, and integrative regulatory evidence. MEASUREMENTS AND MAIN RESULTS: We identified 44 independent genome-wide significant PA diameter signals within 39 loci, including 8 variants replicated in FHS, novel associations near FRMD4B, SLC20A2, BORCS7-ASMT, and KCNRG, and 5 signals in conditional analysis including multiple signals at ANO1. Genetic effects were concordant across imaging modalities and cohorts of differing COPD burden. Effector-gene prioritization nominated ABCC8, PDGFD, HMCN1, CCNE1, and TBX20, implicating pathways in vascular remodeling, developmental regulation, smooth muscle and endothelial function, ion-channel signaling, and extracellular matrix organization. Colocalization with pulse pressure GWAS demonstrated substantial shared causal variation between pulmonary and systemic vascular biology. CONCLUSIONS: In this largest genetic study of pulmonary vascular imaging to date, PA diameter exhibits a polygenic architecture consistent across imaging modalities and cohorts of differing COPD burden. The prioritized effector genes bridge rare-variant pulmonary hypertension biology with common-variant systemic vascular biology.

Pulmonary artery diameter↗

PubMed2000

p53-mediated DNA repair responses to UV radiation: studies of mouse cells lacking p53, p21, and/or gadd45 genes.

Human cells lacking functional p53 exhibit a partial deficiency in nucleotide excision repair (NER), the pathway for repair of UV-induced DNA damage. The global genomic repair (GGR) subpathway of NER, but not transcription-coupled repair (TCR), is mainly affected by p53 loss or inactivation. We have utilized mouse embryo fibroblasts (MEFs) lacking p53 genes or downstream effector genes of the p53 pathway, gadd45 (Gadd45a) or p21 (Cdkn1a), as well as MEFs lacking both gadd45 and p21 genes to address the potential contribution of these downstream effectors to p53-associated DNA repair. Loss of p53 or gadd45 had a pronounced effect on GGR, while p21 loss had only a marginal effect, determined by measurements of repair synthesis (unscheduled DNA synthesis), by immunoassays to detect removal of UV photoproducts from genomic DNA, and by assays determining strand-specific removal of CPDs from the mouse dhfr gene. Taken together, the evidence suggests a role for Gadd45, but relatively little role for p21, in DNA repair responses to UV radiation. Recent evidence suggests that Gadd45 binds to UV-damaged chromatin and may affect lesion accessibility. MEFs lacking p53 or gadd45 genes exhibited decreased colony-forming ability after UV radiation and cisplatin compared to wild-type MEFs, indicating their sensitivity to DNA damage. We provide evidence that Gadd45 affects chromatin remodelling of templates concurrent with DNA repair, thus indicating that Gadd45 may participate in the coupling between chromatin assembly and DNA repair.

Animals↗