Dorothy C Bennett

Dorothy C Bennett
St George's, University of London | SGUL · Molecular and Clinical Sciences Research Institute

MA, PhD, FMedSci

About

257
Publications
90,630
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Introduction
Dot Bennett currently works in (and directs) the Molecular and Clinical Sciences Research Institute, St George's, University of London. Dot's research interests are in cell senescence (in cancer and ageing), and the genetics of melanoma skin cancer, melanocytes and pigmentary disorders. The most recent publication is 'Supplementary Material.'
Additional affiliations
February 2014 - March 2016
St George's, University of London
Position
  • Head of Department
October 1999 - January 2014
St George's, University of London
Position
  • Professor of Cell Biology

Publications

Publications (257)
Article
Full-text available
Mahogunin Ring Finger 1 (MGRN1) is an E3-ubiquitin ligase absent in dark-furred mahoganoid mice. We investigated the mechanisms of hyperpigmentation in Mgrn1-null melan-md1 melanocytes, Mgrn1-KO cells obtained by CRISPR-Cas9-mediated knockdown of Mgrn1 in melan-a6 melanocytes, and melan-a6 cells depleted of MGRN1 by siRNA treatment. Mgrn1-deficient...
Article
Full-text available
Membrane transport carriers fuse with target membranes through engagement of cognate vSNAREs and tSNAREs on each membrane. How vSNAREs are sorted into transport carriers is incompletely understood. Here we show that VAMP7, the vSNARE for fusing endosome-derived tubular transport carriers with maturing melanosomes in melanocytes, is sorted into tran...
Article
Full-text available
The mouse mahoganoid mutation abrogating Mahogunin Ring Finger-1 (MGRN1) E3 ubiquitin ligase expression causes hyperpigmentation, congenital heart defects and neurodegeneration. To study the pathophysiology of MGRN1 loss, we compared Mgrn1-knockout melanocytes with genetically matched controls and melan-md1 (mahoganoid) melanocytes. MGRN1 knockout...
Article
Full-text available
Background: Atypical melanocytic tumors (AMTs) include a wide spectrum of melanocytic neoplasms that represent a challenge for clinicians due to the lack of a definitive diagnosis and the related uncertainty about their management. This study analyzed clinicopathologic features and sentinel node status as potential prognostic factors in patients w...
Article
SLC45A2 encodes a putative transporter expressed primarily in pigment cells. SLC45A2 mutations cause oculocutaneous albinism type IV (OCA4) and polymorphisms are associated with pigmentation variation, but the localization, function, and regulation of SLC45A2 and its variants remain unknown. We show that SLC45A2 localizes to a cohort of mature mela...
Preprint
Mutations of WDR11 are associated with Kallmann syndrome (KS) and congenital hypogonadotrophic hypogonadism (CHH), typically caused by defective functions of gonadotrophin-releasing hormone (GnRH) neurones in the brain. We previously reported that Wdr11 knockout mice show profound infertility with significantly fewer germ cells present in the gonad...
Article
PURPOSE Thin melanomas (T1; ≤ 1 mm) constitute 70% of newly diagnosed cutaneous melanomas. Regional node metastasis determined by sentinel node biopsy (SNB) is an important prognostic factor for T1 melanoma. However, current melanoma guidelines do not provide clear indications on when to perform SNB in T1 disease and stress an individualized approa...
Preprint
SLC45A2 encodes a putative transporter expressed primarily in pigment cells. SLC45A2 mutations and polymorphisms cause oculocutaneous albinism (OCA) and pigmentation variation, but neither SLC45A2 localization and function nor how gene variants affect these properties are known. We show that SLC45A2 localizes to mature melanosomes that only partial...
Article
Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of age-related diseases. Recently, interest in therapeutically targeting senescence to improve healthy aging and age-related disease, otherwise known as senotherapy, has been growing rapidly. Thus, the accurate detection of senescent cells, especia...
Article
Cerebral small vessel disease (cSVD) in penetrating arteries is a major cause of age-related morbidity. Cellular senescence is a molecular process targeted by novel senolytic drugs. We quantified se-nescence in penetrating arteries and tested whether myocyte senescence was associated with cSVD. We immunolabeled subcorti-cal white matter of older pe...
Article
Co‐inheritance of germline mutation in cyclin‐dependent kinase inhibitor 2A (CDKN2A) and loss‐of‐function (LOF) melanocortin 1 receptor (MC1R) variants is clinically associated with exaggerated risk for melanoma. To understand the combined impact of these mutations, we established and tested primary human melanocyte cultures from different CDKN2A m...
Article
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TERT (telomerase reverse transcriptase) is the catalytic component of telomerase. TERT shows little expression in normal somatic cells but is commonly re-expressed in cancers, facilitating immortalization. Recently-discovered TERT promoter mutations create binding sites for ETS-family transcription factors to upregulate TERT. ETS1 is reported to be...
Chapter
Cutaneous melanoma is a deadly skin cancer that affects over 200 000 people worldwide each year. Progression from a normal melanocyte to a metastatic melanoma typically occurs in a step-wise manner, where each stage results from the de-regulation of certain cell signalling pathways. Cellular senescence is known to play a critical role in melanoma s...
Article
Full-text available
Senescence is a universal barrier to immortalisation and tumorigenesis. As such, interest in the use of senescence-induction in a therapeutic context has been gaining momentum in the past few years; however, senescence and immortalisation remain underserved areas for drug discovery owing to a lack of robust senescence inducing agents and an incompl...
Data
Expression of senescence biomarkers allows validation and refinement of screen hits. Validation of the top 40 hit siRNAs for nuclear area increase in A375P (a) and HCT116 (b) ranked in descending order. Mean nuclear area per well (μm2) for triplicate wells in 3 independent transfections is represented as box whisker plots generated in Tableau deskt...
Data
Set-up of a morphology based screen for siRNAs inducing a senescent phenotype. (a) Screen overview. A375P melanoma cells were transfected with 50nM siRNA from the Ambion Druggable Genome Library. 5 days later cells were fixed, stained for DAPI and imaged using the Operetta high content imaging platform. Nuclei in acquired images were detected and q...
Data
A large-scale morphology screen identifies siRNAs that induce a senescent-like morphology in A375P melanoma cells. (a) Scatterplot showing results of a rescreen of 810 siRNAs representing all 3 siRNA oligos included in the Ambion druggable genome library for the top 270 gene hits in A375P. (b) Scatterplot showing the position of all 3 siRNAs target...
Data
Expression of p21 and 53BP1 associated with senescence inducing siRNAs. Representative images of p21 (top) and 53BP1 (bottom) staining for siRNA hits and scrambled controls in A375P (a) and HCT116 (b). (TIF)
Data
Supporting methods, figure legends, and tables. Supporting methods include details of cell lines and culture methods, siRNA transfection methods, screen set-up, statistical analyses and antibodies. Supporting table A shows Operetta analysis sequences and algorithms used. Supporting table B shows parameters used for ArrayScan analysis. (DOCX)
Data
Caspase 3/7 activity and ECT2 levels after ECT2 knockdown in KRAS mutant HCT116 parental cells. (a) Promega Apo-ONE caspase 3/7 assay in HCT116 parental cells. Cells were left untransfected (cells) or were transfected with ECT2, CDK1, or scrambled siRNA. Cell culture medium was included as negative control. Assays were performed 5 days post-transfe...
Data
Validation of the cellular senescence screen. This file provides details of assays performed using etoposide and a kinase inhibitor library to determine optimal phenotypic parameters for use in the screen. Senescence was initially evaluated in A375P cells by a range of assays including growth, colony formation, SAβGal, p21 and 53BP1, H2AX and nucle...
Article
Full-text available
Mutations in SOX10 cause neurocristopathies which display varying degrees of hypopigmentation. Using a sensitized mutagenesis screen, we identified Smarca4 as a modifier gene that exacerbates the phenotypic severity of Sox10 haplo-insufficient mice. Conditional deletion of Smarca4 in SOX10 expressing cells resulted in reduced numbers of cranial and...
Article
Vitiligo is an autoimmune disease in which depigmented skin results from the destruction of melanocytes, with epidemiological association with other autoimmune diseases. In previous linkage and genome-wide association studies (GWAS1 and GWAS2), we identified 27 vitiligo susceptibility loci in patients of European ancestry. We carried out a third GW...
Article
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Endomembrane organelle maturation requires cargo delivery via fusion with membrane transport intermediates and recycling of fusion factors to their sites of origin. Melanosomes and other lysosome-related organelles obtain cargoes from early endosomes, but the fusion machinery involved and its recycling pathway are unknown. Here, we show that the v-...
Article
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Late SV40 factor 3 (LSF), a transcription factor, contributes to human hepatocellular carcinoma (HCC). However, decreased expression level of LSF in skin melanoma compared to that in benign melanocytic tumors and nevi in mice and humans was found in this study. Anchorage-dependent and -independent growth of melanoma cells was suppressed by LSF over...
Article
There are many links between cell senescence and the genetics of melanoma, meaning both familial susceptibility and somatic-genetic changes in sporadic melanoma. For example CDKN2A, the best-known melanoma susceptibility gene, encodes two effectors of cell senescence, while other familial melanoma genes are related to telomeres and their maintenanc...
Article
Full-text available
SOX10 is required for melanocyte development and maintenance, and has been linked to melanoma initiation and progression. However, the molecular mechanisms by which SOX10 guides the appropriate gene expression programs necessary to promote the melanocyte lineage are not fully understood. Here we employ genetic and epigenomic analysis approaches to...
Article
Full-text available
Cellular senescence is a widespread stress response and is widely considered to be an alternative cancer therapeutic goal. Unlike apoptosis, senescence is composed of a diverse set of subphenotypes; depending on which of its associated effector programs are engaged. Here we establish a simple and sensitive, cell-based, prosenescence screen with det...
Article
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Hermansky-Pudlak syndrome (HPS) is a group of disorders characterized by the malformation of lysosome-related organelles, such as pigment cell melanosomes. Three of nine characterized HPS subtypes result from mutations in subunits of BLOC-2, a protein complex with no known molecular function. In this paper, we exploit melanocytes from mouse HPS mod...
Article
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The high mortality of melanoma is caused by rapid spread of cancer cells, which occurs unusually early in tumour evolution. Unlike most solid tumours, thickness rather than cytological markers or differentiation is the best guide to metastatic potential. Multiple stimuli that drive melanoma cell migration have been described, but it is not clear wh...
Article
Located in the basal epidermis and hair follicles, melanocytes of the integument are responsible for its coloration through production of melanin pigments. Melanin is produced in lysosomal-like organelles called melanosomes. In humans, this skin pigmentation acts as an ultraviolet radiation filter. Abnormalities in the division of melanocytes are q...
Article
Little is known as to how cells ensure that organelle size and number are coordinated to correctly couple organelle biogenesis to the demands of proliferation or differentiation. OA1 is a melanosome-associated G-protein-coupled receptor involved in melanosome biogenesis during melanocyte differentiation. Cells lacking OA1 contain fewer, but larger,...
Article
Full-text available
Melanomas are highly lethal skin tumours that are frequently treated by surgical resection. However, the efficacy of such procedures is often limited by tumour recurrence and metastasis. Caveolin-1 (CAV1) has been attributed roles as a tumour suppressor, although in late-stage tumours, its presence is associated with enhanced metastasis. The expres...
Article
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Senescence is a stress-responsive form of stable cell cycle exit. Senescent cells have a distinct gene expression profile, which is often accompanied by the spatial redistribution of heterochromatin into senescence-associated heterochromatic foci (SAHFs). Studying a key component of the nuclear lamina lamin B1 (LMNB1), we report dynamic alterations...
Article
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Some solid tumors have reduced posttranscriptional RNA editing by adenosine deaminase acting on RNA (ADAR) enzymes, but the functional significance of this alteration has been unclear. Here, we found the primary RNA-editing enzyme ADAR1 is frequently reduced in metastatic melanomas. In situ analysis of melanoma samples using progression tissue micr...
Data
Table S1. Numbers of successfully immunostained lesions by antibody and diagnostic category Figure S1. Established ATM/CHEK2 pathways: summary Figure S2. Supporting data for Figure 2 Figure S3. RGB blue channel from all panels of Figure 4
Article
The best-established function of the melanoma-suppressor p16 is mediation of cell senescence, a permanent arrest following cell proliferation or certain stresses. The importance of p16 in melanoma suggests indolence of the other major senescence pathway through p53. Little or no p53 is expressed in senescent normal human melanocytes, but p16-defici...
Article
Full-text available
Cell types that generate unique lysosome-related organelles (LROs), such as melanosomes in melanocytes, populate nascent LROs with cargoes that are diverted from endosomes. Cargo sorting toward melanosomes correlates with binding via cytoplasmically exposed sorting signals to either heterotetrameric adaptor AP-1 or AP-3. Some cargoes bind both adap...
Article
We previously reported a genome-wide association study (GWAS) identifying 14 susceptibility loci for generalized vitiligo. We report here a second GWAS (450 individuals with vitiligo (cases) and 3,182 controls), an independent replication study (1,440 cases and 1,316 controls) and a meta-analysis (3,187 cases and 6,723 controls) identifying 13 addi...