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Article
| Open Access
Fundamental immune–oncogenicity trade-offs define driver mutation fitness
A mathematical framework to estimate the fitness of cancer driver mutations by integrating mutational bias, oncogenicity and immunogenicity finds fundamental trade-offs in cancer evolution.
- David Hoyos
- , Roberta Zappasodi
- & Benjamin D. Greenbaum
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Article
| Open Access
The structure of neurofibromin isoform 2 reveals different functional states
Cryo-EM structure of Nf1 protein is reported, revealing closed and open conformations that regulate interaction with Ras oncogene, setting the stage for understanding the mechanistic action of Nf1 and how disease mutations lead to dysfunction.
- Andreas Naschberger
- , Rozbeh Baradaran
- & Marta Carroni
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Article |
UTX condensation underlies its tumour-suppressive activity
Phase separation properties are a major determinant of UTX activity in chromatin regulation in tumour suppression, and are dependent on a core intrinsically disordered region of the protein.
- Bi Shi
- , Wei Li
- & Hao Jiang
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Article |
DAXX represents a new type of protein-folding enabler
A protein chaperone system is identified that consists of proteins with poly-Asp/Glu sequence, and may have an important role in diseases characterized by protein aggregation.
- Liangqian Huang
- , Trisha Agrawal
- & Xiaolu Yang
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Article |
Replication stress promotes cell elimination by extrusion
A cell-cycle checkpoint triggers the extrusion of both nematode and mammalian cells experiencing replication stress.
- Vivek K. Dwivedi
- , Carlos Pardo-Pastor
- & H. Robert Horvitz
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Article |
AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity
AMBRA1-mediated degradation of cyclin D through CRL4–DDB1 regulates cell proliferation and prevents replication stress in neurodevelopment and cancer.
- Emiliano Maiani
- , Giacomo Milletti
- & Francesco Cecconi
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Article |
Phase and context shape the function of composite oncogenic mutations
Composite mutations, of two or more nonsynonymous somatic mutations in the same cancer-associated gene, are present in nearly one in four human tumours.
- Alexander N. Gorelick
- , Francisco J. Sánchez-Rivera
- & Barry S. Taylor
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Article |
Gasdermin E suppresses tumour growth by activating anti-tumour immunity
The gasdermin E protein is shown to act as a tumour suppressor: it is cleaved by caspase 3 and granzyme B and leads to pyroptosis of cancer cells, provoking an immune response to the tumour.
- Zhibin Zhang
- , Ying Zhang
- & Judy Lieberman
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Article |
DNA clamp function of the monoubiquitinated Fanconi anaemia ID complex
Cryo-EM structures of the FANCI–FANCD2 complex bound to DNA reveal that monoubiquitination triggers structural changes that enable the complex to function as a sliding DNA clamp and coordinate the repair of DNA interstrand crosslinks.
- Renjing Wang
- , Shengliu Wang
- & Nikola P. Pavletich
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Letter |
α-Ketoglutarate links p53 to cell fate during tumour suppression
Restoring the function of p53 in a mouse model of pancreatic ductal adenocarcinoma leads to the accumulation of α-ketoglutarate, which increases levels of the 5-hydroxymethylcytosine chromatin modification and results in reduced tumour-cell fitness.
- John P. Morris IV
- , Jossie J. Yashinskie
- & Scott W. Lowe
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Letter |
Tumour lineage shapes BRCA-mediated phenotypes
Analysis of more than 17,000 tumours suggests that the contribution of germline and somatic mutations in the BRCA1 and BRCA2 genes to oncogenesis depends on tumour lineage.
- Philip Jonsson
- , Chaitanya Bandlamudi
- & Barry S. Taylor
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Letter |
RB constrains lineage fidelity and multiple stages of tumour progression and metastasis
Loss of RB promotes both malignant progression and the development of metastatic disease; however, whereas reactivation of the RB pathway can revert metastatic tumour cell states to non-metastatic cell states, malignant cell proliferation is supported by MAPK–CDK2-dependent suppression of RB.
- David M. Walter
- , Travis J. Yates
- & David M. Feldser
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Letter |
Widespread intronic polyadenylation inactivates tumour suppressor genes in leukaemia
The inactivation of tumour suppressor genes at the level of mRNA occurs by the generation of truncated proteins in leukaemia.
- Shih-Han Lee
- , Irtisha Singh
- & Christine Mayr
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Letter |
Structures of human Patched and its complex with native palmitoylated sonic hedgehog
High-resolution structures of the human plasma membrane protein patched 1 alone and in complex with the native form of the ligand sonic hedgehog are determined.
- Xiaofeng Qi
- , Philip Schmiege
- & Xiaochun Li
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Letter |
The protein histidine phosphatase LHPP is a tumour suppressor
Decreased expression of histidine phosphatase LHPP, a novel tumour suppressor, results in increased global histidine phosphorylation and hepatocellular carcinoma.
- Sravanth K. Hindupur
- , Marco Colombi
- & Michael N. Hall
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Letter |
Cyclin D–CDK4 kinase destabilizes PD-L1 via cullin 3–SPOP to control cancer immune surveillance
Abundance of PD-L1, the ligand of the anti-cancer immunotherapy target PD-1, is negatively regulated by poly-ubiquitination via the cyclin D–CDK4/cullin 3–SPOP axis and PD-1 blockade treatment in mice improved survival when combined with CDK4/6 inhibitors.
- Jinfang Zhang
- , Xia Bu
- & Wenyi Wei
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Article |
BRCA1–BARD1 promotes RAD51-mediated homologous DNA pairing
The tumour suppressor complex BRCA1–BARD1, which facilitates the generation of a single-stranded DNA template during homologous recombination, also binds to the recombinase RAD51 and enhances its function.
- Weixing Zhao
- , Justin B. Steinfeld
- & Patrick Sung
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Letter |
ERF mutations reveal a balance of ETS factors controlling prostate oncogenesis
In prostate cancer, the oncogenicity of transcription factor ERG is mediated, in part, by competition with another member of the ETS family, ERF.
- Rohit Bose
- , Wouter R. Karthaus
- & Charles L. Sawyers
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Article |
LACTB is a tumour suppressor that modulates lipid metabolism and cell state
LACTB modulates mitochondrial lipid metabolism and changes the differentiation state of breast cancer cells, thereby negatively affecting the growth of various tumorigenic, but not non-tumorigenic, cells both in vitro and in vivo.
- Zuzana Keckesova
- , Joana Liu Donaher
- & Robert A. Weinberg
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Article |
LKB1 loss links serine metabolism to DNA methylation and tumorigenesis
Human tumours with mutations in LKB1 and Kras have a specific hypermetabolic state associated with increased DNA methylation, pointing to potential metabolic and epigenetic vulnerabilities of specific tumours.
- Filippos Kottakis
- , Brandon N. Nicolay
- & Nabeel Bardeesy
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Letter |
Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode
The acidic domain of SET binds and represses unacetylated p53, but this interaction is prevented by cellular-stress-induced p53 CTD acetylation.
- Donglai Wang
- , Ning Kon
- & Wei Gu
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Letter |
On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models
The small-molecule HIF-2α antagonist PT2399 causes tumour regression in animal models of clear cell renal cell carcinoma, but cell lines of this tumour type show unexpectedly variable responses to PT2399.
- Hyejin Cho
- , Xinlin Du
- & William G. Kaelin
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Letter |
Rad51 paralogues Rad55–Rad57 balance the antirecombinase Srs2 in Rad51 filament formation
- Jie Liu
- , Ludovic Renault
- & Wolf-Dietrich Heyer
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Letter |
SCFFBW7 regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction
This is one of two papers demonstrating that in several cancer types including ovarian cancer and T-cell leukaemias, the apoptosis regulator MCL1 is targeted for degradation by the FBW7 tumour suppressor. This study finds that this mechanism can determine the response to drugs targeting BCL2 family apoptosis factors. Deletion or mutation of FBW7 found in cancer patients therefore can render tumours resistant to these therapies.
- Hiroyuki Inuzuka
- , Shavali Shaik
- & Wenyi Wei
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News & Views |
The blind spot of p53
It is hoped that reactivating the tumour-suppressor protein p53 will help to combat cancer. However, fresh evidence suggests it is unlikely that all cells in a tumour will respond to such treatment. See Letters p.567 & p.572
- Anton Berns
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Letter |
Stage-specific sensitivity to p53 restoration during lung cancer progression
p53 is an important tumour suppressor gene. Two papers now show in a Kras-driven lung cancer model that p53-mediated tumour suppression is only engaged late during tumour progression, when the Kras oncogenic signal reaches a threshold sufficient to activate the ARF–p53 pathway. Therefore, p53 re-expression in p53-deficient lung tumours does not restrict early stages of tumorigenesis, but induces tumour regression of more aggressive tumours.
- David M. Feldser
- , Kamena K. Kostova
- & Tyler Jacks
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News & Views |
A protein giant in its entirety
Purification of the human tumour-suppressor protein BRCA2, which is crucial for DNA repair, has been a formidable challenge owing to its large size. That mission is now accomplished, providing biochemical insight. See Article p.678
- Lee Zou
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News & Views |
Retinoblastoma, a trip organizer
The retinoblastoma protein is essential for accurate DNA replication, and its loss is commonly associated with cancer. It emerges that this protein also regulates another stage of the cell cycle.
- Giovanni Bosco
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Research Highlights |
Genetics: Protein's billion-year history
p53 governs an AT1 differentiation programme in lung cancer suppression