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The BRCA1–BARD1 tumour suppressor is an E3 ubiquitin ligase necessary for the repair of DNA double-strand breaks by homologous recombination 1 – 10 . The BRCA1–BARD1 complex localizes to damaged chromatin after DNA replication and catalyses the ubiquitylation of histone H2A and other cellular targets 11 – 14 . The molecular bases for the recruitment to double-strand breaks and target recognition of BRCA1–BARD1 remain unknown. Here we use cryo-electron microscopy to show that the ankyrin repeat and tandem BRCT domains in BARD1 adopt a compact fold and bind to nucleosomal histones, DNA and monoubiquitin attached to H2A amino-terminal K13 or K15, two signals known to be specific for double-strand breaks 15 , 16 . We further show that RING domains 17 in BRCA1–BARD1 orient an E2 ubiquitin-conjugating enzyme atop the nucleosome in a dynamic conformation, primed for ubiquitin transfer to the flexible carboxy-terminal tails of H2A and variant H2AX. Our work reveals a regulatory crosstalk in which recognition of monoubiquitin by BRCA1–BARD1 at the N terminus of H2A blocks the formation of polyubiquitin chains and cooperatively promotes ubiquitylation at the C terminus of H2A. These findings elucidate the mechanisms of BRCA1–BARD1 chromatin recruitment and ubiquitylation specificity, highlight key functions of BARD1 in both processes and explain how BRCA1–BARD1 promotes homologous recombination by opposing the DNA repair protein 53BP1 in post-replicative chromatin 18 – 22 . These data provide a structural framework to evaluate BARD1 variants and help to identify mutations that drive the development of cancer. The authors elucidate the mechanisms for the ubiquitylation specificity and recruitment of the ubiquitin ligase complex BRCA1–BARD1 to damaged DNA within chromatin to facilitate homologous recombination.

Bone remodeling consists of resorption by osteoclasts followed by formation by osteoblasts, and osteoclasts are a source of bone formation-stimulating factors. Here we utilize osteoclast ablation by denosumab (DMAb) and RNA-sequencing of bone biopsies from postmenopausal women to identify osteoclast-secreted factors suppressed by DMAb. Based on these analyses, LIF, CREG2, CST3, CCBE1 , and DPP4 are likely osteoclast-derived coupling factors in humans. Given the role of Dipeptidyl Peptidase-4 (DPP4) in glucose homeostasis, we further demonstrate that DMAb-treated participants have a significant reduction in circulating DPP4 and increase in Glucagon-like peptide (GLP)-1 levels as compared to the placebo-treated group, and also that type 2 diabetic patients treated with DMAb show significant reductions in HbA1c as compared to patients treated either with bisphosphonates or calcium and vitamin D. Thus, our results identify several coupling factors in humans and uncover osteoclast-derived DPP4 as a potential link between bone remodeling and energy metabolism. Anti-resorptive bone therapies also inhibit bone formation, as osteoclasts secrete factors that stimulate bone formation by osteoblasts. Here, the authors identify osteoclast-secreted factors that couple bone resorption to bone formation in healthy subjects, and show that osteoclast-derived DPP4 may be a factor coupling bone resorption to energy metabolism.

Mutant p53 can attenuate the function of wild-type p53, p63 and p73. An aggregation-nucleating sequence in p53 that is revealed in structurally destabilized mutants can induce coaggregation with p63 and p73, resulting in their sequestration in cellular inclusions. Many p53 missense mutations possess dominant-negative activity and oncogenic gain of function. We report that for structurally destabilized p53 mutants, these effects result from mutant-induced coaggregation of wild-type p53 and its paralogs p63 and p73, thereby also inducing a heat-shock response. Aggregation of mutant p53 resulted from self-assembly of a conserved aggregation-nucleating sequence within the hydrophobic core of the DNA-binding domain, which becomes exposed after mutation. Suppressing the aggregation propensity of this sequence by mutagenesis abrogated gain of function and restored activity of wild-type p53 and its paralogs. In the p53 germline mutation database, tumors carrying aggregation-prone p53 mutations have a significantly lower frequency of wild-type allele loss as compared to tumors harboring nonaggregating mutations, suggesting a difference in clonal selection of aggregating mutants. Overall, our study reveals a novel disease mechanism for mutant p53 gain of function and suggests that, at least in some respects, cancer could be considered an aggregation-associated disease.

Tumor suppressor p53 plays an important role in cancer prevention. Under normal conditions, p53 is maintained at a low level. However, in response to various cellular stresses, p53 is stabilized and activated, which, in turn, initiates DNA repair, cell‐cycle arrest, senescence and apoptosis. Post‐translational modifications of p53 including phosphorylation, ubiquitination, and acetylation at multiple sites are important to regulate its activation and subsequent transcriptional gene expression. Particularly, phosphorylation of p53 plays a critical role in modulating its activation to induce apoptosis in cancer cells. In this context, previous studies show that several serine/threonine kinases regulate p53 phosphorylation and downstream gene expression. The molecular basis by which p53 and its kinases induce apoptosis for cancer prevention has been extensively studied. However, the relationship between p53 phosphorylation and its kinases and how the activity of kinases is controlled are still largely unclear; hence, they need to be investigated. In this review, we discuss various roles for p53 phosphorylation and its responsible kinases to induce apoptosis and a new therapeutic approach in a broad range of cancers. Several serine/threonine kinases regulate p53 phosphorylation and downstream gene expression to induce apoptosis in response to DNA damage. This review discusses various roles for p53 phosphorylation and its responsible kinases to induce apoptosis and a new therapeutic approach in a broad range of cancers.

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3 . In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer. Genomic sequencing of 110 human small cell lung cancers identifies genomic signatures including nearly ubiquitous bi-allelic inactivation of TP53 and RB1 , a role for NOTCH family genes, and somatic rearrangements that create an oncogenic version of TP73 . Genetic causes of small cell lung cancer Whole-genome sequencing of 110 small cell lung cancers reveals a characteristic bi-allelic inactivation of the tumour suppressor genes TP53 and RB1 in almost all cases. In the only two specimens with no alterations in TP53 and RB1 , chromothripsis activates cyclin D1, leading to the same molecular effect. In addition, 25% of tumours carry inactivating mutations in NOTCH family genes, and the authors show that activation of Notch signalling in a pre-clinical mouse model reduces the number of tumours and extends the survival of the mutant mice. This work highlights possible drug targets in one of the deadliest of human cancers.

N 6 -methyladenosine (m 6 A) is the most abundant mRNA modification and is catalyzed by the methyltransferase complex, in which methyltransferase-like 3 (METTL3) is the sole catalytic subunit. Accumulating evidence in recent years reveals that METTL3 plays key roles in a variety of cancer types, either dependent or independent on its m 6 A RNA methyltransferase activity. While the roles of m 6 A modifications in cancer have been extensively reviewed elsewhere, the critical functions of METTL3 in various types of cancer, as well as the potential targeting of METTL3 as cancer treatment, have not yet been highlighted. Here we summarize our current understanding both on the oncogenic and tumor-suppressive functions of METTL3, as well as the underlying molecular mechanisms. The well-documented protein structure of the METTL3/METTL14 heterodimer provides the basis for potential therapeutic targeting, which is also discussed in this review.

Key Points The role of tumour suppressors in immunity is strongly linked to maintenance of genomic integrity. Impaired expression of tumour suppressor genes such as those that encode p53, retinoblastoma-associated gene 1 (RB1), phosphatase and tensin homologue (PTEN) and ARF results in susceptibility to chronic inflammatory responses triggered by pathogens and environmental stress. The tumour suppressor p53 and its transcriptional targets are involved in crucial aspects of tumour and pathogen immunology and in homeostatic regulation of immune responses. This pathway has an important role in host immunity influencing both innate and adaptive immune responses. A link between the tumour suppressor p53 and immune checkpoint regulators, including programmed cell death 1 (PD1), PD1 ligand 1 (PDL1) and DD1α, has been identified in cancer cells. Several tumour suppressor genes including those encoding p53, ARF, RB1 and PTEN influence T cell fate by modulating the immune synapse through pattern recognition receptors, cytokine production and expression of MHC and co-inhibitory molecules. Tumour suppressor gene function is emerging as a potential 'guardian of immune integrity'. The tumour suppressor p53 has well-known functions in cell repair and cell death that have led to its title as the 'guardian of the genome'. Here, the authors discuss the less-well appreciated roles of p53 and other tumour suppressor genes in shaping immune responses; they propose that these genes could also be considered to be 'guardians of immune integrity'. Tumour-suppressor genes are indispensable for the maintenance of genomic integrity. Recently, several of these genes, including those encoding p53, PTEN, RB1 and ARF, have been implicated in immune responses and inflammatory diseases. In particular, the p53 tumour- suppressor pathway is involved in crucial aspects of tumour immunology and in homeostatic regulation of immune responses. Other studies have identified roles for p53 in various cellular processes, including metabolism and stem cell maintenance. Here, we discuss the emerging roles of p53 and other tumour-suppressor genes in tumour immunology, as well as in additional immunological settings, such as virus infection. This relatively unexplored area could yield important insights into the homeostatic control of immune cells in health and disease and facilitate the development of more effective immunotherapies. Consequently, tumour-suppressor genes are emerging as potential guardians of immune integrity.

Muller and Vousden discuss the functional outcomes of mutant p53 in cancer and outline the mechanisms through which gain-of-function mutant p53 forms exert their oncogenic effects. In the past fifteen years, it has become apparent that tumour-associated p53 mutations can provoke activities that are different to those resulting from simply loss of wild-type tumour-suppressing p53 function. Many of these mutant p53 proteins acquire oncogenic properties that enable them to promote invasion, metastasis, proliferation and cell survival. Here we highlight some of the emerging molecular mechanisms through which mutant p53 proteins can exert these oncogenic functions.

PDCD4 is a novel tumor suppressor to show multi-functions inhibiting cell growth, tumor invasion, metastasis, and inducing apoptosis. PDCD4 protein binds to the translation initiation factor eIF4A, some transcription factors, and many other factors and modulates the function of the binding partners. PDCD4 downregulation stimulates and PDCD4 upregulation inhibits the TPA-induced transformation of cells. However, PDCD4 gene mutations have not been found in tumor cells but gene expression was post transcriptionally downregulated by micro environmental factors such as growth factors and interleukins. In this review, we focus on the suppression mechanisms of PDCD4 protein that is induced by the tumor promotors EGF and TPA, and in the inflammatory conditions. PDCD4-protein is phosphorylated at 2 serines in the SCFβTRCP ubiquitin ligase binding sequences via EGF and/or TPA induced signaling pathway, ubiquitinated, by the ubiquitin ligase and degraded in the proteasome system. The PDCD4 protein synthesis is inhibited by microRNAs including miR21.

ObjectiveSessile serrated adenomas (SSAs) are the precursors of at least 15% of colorectal carcinomas, but their biology is incompletely understood. We performed a clinicopathological and molecular analysis of a large number of the rarely observed SSAs with dysplasia/carcinoma to better define their features and the pathways by which they progress to carcinoma.DesignA cross-sectional analysis of 137 SSAs containing regions of dysplasia/carcinoma prospectively collected at a community GI pathology practice was conducted. Samples were examined for BRAF and KRAS mutations, the CpG island methylator phenotype (CIMP) and immunostained for MLH1, p53, p16, β-catenin and 0-6-methylguanine DNA methyltransferase (MGMT).ResultsThe median polyp size was 9 mm and 86.5% were proximal. Most were BRAF mutated (92.7%) and 94.0% showed CIMP. Mismatch repair deficiency, evidenced by loss of MLH1 (74.5%) is associated with older age (76.7 versus 71.0; p<0.0029), female gender (70% versus 36%; p<0.0008), proximal location (91% versus 72%; p<0.02), CIMP (98% versus 80%; p<0.02) and lack of aberrant p53 (7% versus 34%; p<0.001) when compared with the mismatch repair-proficient cases. Loss of p16 (43.1%) and gain of nuclear β-catenin (55.5%) were common in areas of dysplasia/cancer, irrespective of mismatch repair status.ConclusionsSSAs containing dysplasia/carcinoma are predominantly small (<10 mm) and proximal. The mismatch repair status separates these lesions into distinct clinicopathological subgroups, although WNT activation and p16 silencing are common to both. Cases with dysplasia occur at a similar age to cases with carcinoma. This, together with the rarity of these ‘caught in the act’ lesions, suggests a rapid transition to malignancy following a long dwell time as an SSA without dysplasia.