Joanna R. Morris

The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress

Mutations in BRCA1 are associated with a high risk of breast and ovarian cancer. BRCA1 participates in the DNA damage response and acts as a ubiquitin ligase. However, its regulation remains poorly understood. Here we report that BRCA1 is modified by small ubiquitin-like modifier (SUMO) in response to genotoxic stress, and co-localizes at sites of DNA damage with SUMO1, SUMO2/3 and the SUMO-conjugating enzyme Ubc9. PIAS SUMO E3 ligases co-localize with and modulate SUMO modification of BRCA1, and are required for BRCA1 ubiquitin ligase activity in cells. In vitro SUMO modification of the BRCA1/BARD1 heterodimer greatly increases its ligase activity, identifying it as a SUMO-regulated ubiquitin ligase (SRUbL). Further, PIAS SUMO ligases are required for complete accumulation of double-stranded DNA (dsDNA) damage-repair proteins subsequent to RNF8 accrual, and for proficient double-strand break repair. These data demonstrate that the SUMOylation pathway plays a significant role in mammalian DNA damage response.

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

IntroductionBreast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice.MethodsMore than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer ‘stem’ cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account.ResultsThe 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working.ConclusionsWith resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years.

BRCA1 RING function is essential for tumor suppression but dispensable for therapy resistance.

Hereditary breast cancers are frequently caused by germline BRCA1 mutations. The BRCA1(C61G) mutation in the BRCA1 RING domain is a common pathogenic missense variant, which reduces BRCA1/BARD1 heterodimerization and abrogates its ubiquitin ligase activity. To investigate the role of BRCA1 RING function in tumor suppression and therapy response, we introduced the Brca1(C61G) mutation in a conditional mouse model for BRCA1-associated breast cancer. In contrast to BRCA1-deficient mammary carcinomas, tumors carrying the Brca1(C61G) mutation responded poorly to platinum drugs and PARP inhibition and rapidly developed resistance while retaining the Brca1(C61G) mutation. These findings point to hypomorphic activity of the BRCA1-C61G protein that, although unable to prevent tumor development, affects response to therapy.

Total tooth loss in the United Kingdom in 1998 and implications for the future.

The 1998 Adult Dental Health Survey, published this year, showed that the number of people without teeth should fall over the next three decades, to only 4% of the UK population. Patterns of tooth loss and retention are also changing. This article, the first of a series on the interpretation of the Adult Dental Health Survey, discusses the implications of these trends for dentistry.

Dental attendance in 1998 and implications for the future.

The 1998 survey of Adult Dental Health in the UK was carried out under the auspices of the Office of National Statistics together with the Universities of Birmingham, Dundee, Newcastle-upon-Tyne and Wales. A key behavioural indicator in these decennial surveys is whether people say they go to a dentist for a regular dental check-up, an occasional dental check-up or only when they have trouble with their teeth. The proportion of dentate adults in the UK who report attending for regular dental check-ups has risen from 43% in 1978 to 59% in 1998. Older adults (over 55 years old) in 1998 were the most likely to say they attend for regular dental check-ups. Many younger adults (16-24) in 1998 said they went to a dentist less often than 5 years previously, they were also the least likely to say they attend for regular dental check-ups. Dental anxiety remains a problem for many dental patients but another factor of importance to many is their want to be involved in the treatment process and especially to be given an estimate of treatment costs.

BRCA1 methylation: a significant role in tumour development?

Cancer is a multistep process resulting from an accumulation of genetic mutations leading to dysfunction of critical genes, including tumour suppressor genes. Epigenetic changes are now also recognised as an important alternative mechanism of gene inactivation. In particular, aberrant methylation of the promoter region of a gene can lead to silencing ultimately contributing to the initiation or malignant progression of tumours. BRCA1, a breast and ovarian cancer susceptibility gene, is a tumour suppressor gene involved in the maintenance of genome integrity. Recent evidence for BRCA1 hypermethylation corroborates the view that this epigenetic alteration may play a determinant role in tumour suppressor silencing and possibly tumorigenesis. Here, we offer a summary of the data providing evidence for BRCA1 hypermethylation in tumours, and an investigation into the associated mechanism leading to BRCA1 silencing. We also discuss the impact of BRCA1 hypermethylation, as a form of epigenetic change, versus BRCA1 genetic mutations in tumour development.

The proteasomal de‐ubiquitinating enzyme POH1 promotes the double‐strand DNA break response

The regulation of Ubiquitin (Ub) conjugates generated by the complex network of proteins that promote the mammalian DNA double‐strand break (DSB) response is not fully understood. We show here that the Ub protease POH1/rpn11/PSMD14 resident in the 19S proteasome regulatory particle is required for processing poly‐Ub formed in the DSB response. Proteasome activity is required to restrict tudor domain‐dependent 53BP1 accumulation at sites of DNA damage. This occurs both through antagonism of RNF8/RNF168‐mediated lysine 63‐linked poly‐Ub and through the promotion of JMJD2A retention on chromatin. Consistent with this role POH1 acts in opposition to RNF8/RNF168 to modulate end‐joining DNA repair. Additionally, POH1 acts independently of 53BP1 in homologous recombination repair to promote RAD51 loading. Accordingly, POH1‐deficient cells are sensitive to DNA damaging agents. These data demonstrate that proteasomal POH1 is a key de‐ubiquitinating enzyme that regulates ubiquitin conjugates generated in response to damage and that several aspects of the DSB response are regulated by the proteasome.

adult dental health survey: Total tooth loss in the United Kingdom in 1998 and implications for the future

The 1998 Adult Dental Health Survey, published this year, showed that the number of people without teeth should fall over the next three decades, to only 4% of the UK population. Patterns of tooth loss and retention are also changing. This article, the first of a series on the interpretation of the Adult Dental Health Survey, discusses the implications of these trends for dentistry.

Adult Dental Health Survey 2009: transformations in British oral health 1968-2009

This series of four papers reports and interprets the findings of the Adult Dental Health Survey (ADHS), 2009, published in early 2011. This is the fifth in a series of surveys repeated every decade since 1968. The evolution of the surveys and the way the supporting methodology has changed to meet the changing needs and circumstances over the last 40 years is described. In 1968, 37% of adults in England and Wales were edentate. By 2009, only 6% of the combined population of England, Wales and Northern Ireland were edentate. Among the dentate in 1968, there were a mean of 21.9 teeth. By 2009, not only had the dentate increased by 30 percentage points as a fraction of the population, but the number of teeth in this group had also increased by nearly four teeth on average to 25.7. There were significant variations in oral health according to geography and social variables and smaller differences according to sex. The retention of 21 or more teeth is widely used as a way of defining a minimum functional dentition. The proportion of adults with 21+ teeth increased from 73% in 1978 to 86% in 2009. Further huge improvements are projected as younger generations age, assuming future tooth loss continues at current low rates. We might expect that over 90% of those aged 35-44 in 2009 have a realistic prospect of retaining a functional natural dentition of 21 or more teeth by age 80.

The condition of teeth in the UK in 1998 and implications for the future.

The latest of the decennial surveys of the United Kingdom was undertaken in 1998 by the Office of National Statistics in collaboration with the dental schools of the Universities of Birmingham, Dundee, Newcastle and Wales. Dentate adults in 1998 have fewer missing teeth and more sound and untreated teeth on average than in 1978. The average number of decayed teeth has dropped significantly from 1.9 in 1978 to 1.1 in 1998. The average number of filled teeth has remained fairly constant over the same time but its distribution has changed quite markedly towards older adults having more filled teeth than people of a similar age in the past whilst the reverse is true for younger adults. The overall trends are encouraging, but there is a need to review the way disease is managed in adults in the United Kingdom.