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Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle
A major problem in the treatment of bone tumours and metastases is the vicious cycle between bone tumours and resorption. Here, the authors show that treatment with the BET bromodomain inhibitor JQ1 inhibits osteoblast and osteoclast differentiation, and bone tumour development.
- François Lamoureux
- , Marc Baud’huin
- & Benjamin Ory
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| Open AccessLigand substitutions between ruthenium–cymene compounds can control protein versus DNA targeting and anticancer activity
Ruthenium-cymene-based compounds are investigated as potential anticancer drugs. Here, Adhireksan et al.study two ruthenium-containing compounds with varying cytotoxicity and show that differences in ligand structure may explain their activity and binding to different subcellular targets.
- Zenita Adhireksan
- , Gabriela E. Davey
- & Curt A. Davey
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MTSS1 is a metastasis driver in a subset of human melanomas
Complex genomic alterations segregate melanoma into different molecular subsets, but for most subsets it is unclear whether they drive a distinct clinical behaviour. Here, the authors use gene-expression data from melanoma patients to search for outlier genes that correlate with survival and identify that MTSS1 is associated with metastasis.
- Kirsten D. Mertz
- , Gaurav Pathria
- & Stephan N. Wagner
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| Open AccessReduced methylation of PFKFB3 in cancer cells shunts glucose towards the pentose phosphate pathway
Haem oxygenase 1 produces carbon monoxide and this byproduct is known to alter cellular signalling. Here, the authors show that carbon monoxide alters the methylation of PFKFB3 in cancer cells resulting in deregulated cellular metabolism and the shunting of glucose into the pentose phosphate pathway.
- Takehiro Yamamoto
- , Naoharu Takano
- & Makoto Suematsu
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Skp2 suppresses apoptosis in Rb1-deficient tumours by limiting E2F1 activity
The pRb target E2F1 possesses contradictory activities in promoting proliferation and apoptosis. Here, the authors define a pRb-Skp2-p27-cyclin A-E2F1 survival pathway that can be disrupted to prevent Rb1-deficient tumorigenesis in the pituitary intermediate lobe.
- Zhonglei Lu
- , Frederick Bauzon
- & Liang Zhu
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2′-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity
Short interfering siRNAs—siRNAs—have therapeutic potential in the treatment of disease; however, their delivery to target tissues is difficult. Here, Wu et al. chemically modify siRNAs and show that this improves loading into the siRNA silencing machinery and thus efficacy in eliminating cancer cells in mice.
- Sherry Y. Wu
- , Xianbin Yang
- & Anil K. Sood
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ATP-triggered anticancer drug delivery
Nanoparticles can deliver drugs to tumours but improvements in selectively targeting tumour cells are required. Here, Mo et al. develop nanocarriers that take advantage of high ATP levels in tumour cells and show that these nanoparticles encapsulating the chemotherapeutic doxorubicin can inhibit tumour growth in mice.
- Ran Mo
- , Tianyue Jiang
- & Zhen Gu
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Nuclear receptor NR4A1 promotes breast cancer invasion and metastasis by activating TGF-β signalling
The TGF-β signalling pathway promotes cancer progression in late stage breast cancer, but how the pathway is activated is not always clear. In this study, Zhou et al.identify that the expression of nuclear receptor NR4A1 is induced by inflammation and is an activator of TGF-β-induced metastasis.
- FangFang Zhou
- , Yvette Drabsch
- & Peter ten Dijke
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Characterizing the genetic basis of methylome diversity in histologically normal human lung tissue
The effects of genetic variation on DNA methylation patterns are poorly understood. Here, Shi et al.systematically map methylation-quantitative trait loci in lung, breast and kidney tissue to reveal the impact of inherited variation on the human methylome, which also affects cancer risk.
- Jianxin Shi
- , Crystal N. Marconett
- & Maria Teresa Landi
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Bio-barcode gel assay for microRNA
MicroRNA has been identified to play a role in cancer development, thus its detection at low concentrations would be a highly beneficial diagnostic tool. Here, the authors develop a gel-based bio-barcode assay for microRNA detection using DNA-modified gold nanoparticles, with aM limits of detection.
- Hyojin Lee
- , Jeong-Eun Park
- & Jwa-Min Nam
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Telomerase reverse transcriptase promoter mutations in primary cutaneous melanoma
Cutaneous melanoma is an aggressive form of skin cancer. Here, the authors show that mutations in the TERT promoter of 287 primary melanomas are associated with age, Breslow thickness and tumour ulceration and frequently occur at sun-exposed sites.
- Barbara Heidenreich
- , Eduardo Nagore
- & Rajiv Kumar
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Loss of NDRG2 expression activates PI3K-AKT signalling via PTEN phosphorylation in ATLL and other cancers
The PI3K pathway that encompasses the tumour suppressor PTEN contributes to tumourigenesis in adult T-cell leukaemia-lymphoma (ATLL). In this study, Nakahata et al. show that PTEN is dephosphorylated by NDRG2, and that loss of NDGR2 in ATLL results in the activation of the PI3K pathway.
- Shingo Nakahata
- , Tomonaga Ichikawa
- & Kazuhiro Morishita
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Genome-wide transcriptome profiling of homologous recombination DNA repair
Defects in the homologous recombination repair of DNA can result in gene mutation and cancer. In this study, Peng et al.identify a gene signature associated with homologous recombination repair deficiency and show that this can be used both to predict repair defects and clinical outcome in cancer patients.
- Guang Peng
- , Curtis Chun-Jen Lin
- & Shiaw-Yih Lin
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| Open AccessThe DUSP26 phosphatase activator adenylate kinase 2 regulates FADD phosphorylation and cell growth
Adenylate kinase 2 can bind to FADD. In this study, Kim et al.show that adenylate kinase 2 is a tumour suppressor and interacts with the phosphatase DUSP6, and this in turn regulates the phosphorylation of FADD.
- Hyunjoo Kim
- , Ho-June Lee
- & Yong-Keun Jung
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| Open AccessInduction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments
Quiescent sub-populations of cells in tumours are resistant to traditional chemotherapeutics and are responsible for tumour recurrence. Here, Zhang et al. identify a compound that kills quiescent tumour cells in solid tumour tissue by inducing mitochondrial dysfunction.
- Xiaonan Zhang
- , Mårten Fryknäs
- & Stig Linder
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| Open AccessIdentification of renin progenitors in the mouse bone marrow that give rise to B-cell leukaemia
Renin cells have traditionally been associated with the kidney where they regulate blood pressure and fluid electrolyte homeostasis. In this study, Belyea et al.describe a renin progenitor in the bone marrow that gives rise to B-cell leukaemia when RBP-J, the final effector of the Notch pathway, is deleted.
- Brian C. Belyea
- , Fang Xu
- & R. Ariel Gomez
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| Open AccessTransdifferentiation of lung adenocarcinoma in mice with Lkb1 deficiency to squamous cell carcinoma
Non-small cell lung cancer manifests as adenocarcinoma and squamous cell carcinoma but tumours of mixed lineage are often found in humans. Here, the authors show that adenocarcinoma can transdifferentiate into squamous cell carcinomas in mice.
- Xiangkun Han
- , Fuming Li
- & Hongbin Ji
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USP11 regulates PML stability to control Notch-induced malignancy in brain tumours
The tumour suppressor PML is regulated by post-translational modification but the mechanism is unclear. Here, the authors show that PML is deubiquitinated and stabilized by USP11, which is in turn negatively regulated by the Notch signalling pathway.
- Hsin-Chieh Wu
- , Yu-Ching Lin
- & Ruey-Hwa Chen
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Gene co-expression network analysis reveals common system-level properties of prognostic genes across cancer types
Many studies provide evidence of genes that are associated with cancer prognosis but a global view of these genes is lacking. Using data from ‘The Cancer Genome Atlas’, Yang et al.investigate the network properties of prognostic genes and show that these genes tend to be within highly interconnected groups but not the most connected nodes in the gene co-expression network.
- Yang Yang
- , Leng Han
- & Han Liang
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RSPO2–LGR5 signaling has tumour-suppressive activity in colorectal cancer
R-spondin 2 has an important role in development but its function in cancer has not been described. In this study, Wu et al. demonstrate that R-spondin 2 is decreased in expression in colorectal cancer and this is associated with promoter methylation and inhibition of Wnt signalling.
- Changjie Wu
- , Sunquan Qiu
- & Xincheng Lu
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SLAP displays tumour suppressor functions in colorectal cancer via destabilization of the SRC substrate EPHA2
SLAP is an adaptor protein that negatively regulates receptor signalling, but its involvement in cancer has not been described. In this study, Naudin et al. demonstrate that SLAP negatively regulates the receptor EphA2 in a Src-dependent manner and is reduced in expression in colorectal cancer.
- Cécile Naudin
- , Audrey Sirvent
- & Serge Roche
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Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer
Cellular metabolism is dysregulated in cancer and may be reflected in differences in the expression of metabolic genes. In this study, the authors find that mitochondrial folate-coupled dehydrogenase is increased in expression in a wide variety of cancers and negatively correlates with breast cancer patient survival.
- Roland Nilsson
- , Mohit Jain
- & Vamsi K. Mootha
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The miR-363-GATA6-Lgr5 pathway is critical for colorectal tumourigenesis
Lgr5 is a protein that is important for the maintenance of intestinal homeostasis. In this study, the authors demonstrate that Lgr5 is required for colorectal cancer development and its expression is regulated by the transcription factor GATA6.
- Shinnosuke Tsuji
- , Yoshihiro Kawasaki
- & Tetsu Akiyama
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Integrated analysis of germline and somatic variants in ovarian cancer
Ovarian cancer is one of the most common cancers in women and has an average 5-year survival of only 43%. Here, Kanchi et al.describe the germline and somatic mutation spectrum in ovarian cancer patients and identify potential risk variants associated with the disease.
- Krishna L. Kanchi
- , Kimberly J. Johnson
- & Li Ding
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Kinase fusions are frequent in Spitz tumours and spitzoid melanomas
Spitzoid neoplasms constitute a spectrum of melanocytic tumours, characterized by distinct clinical, pathological and genetic features. Here, Wiesner et al. show that kinase fusions represent the majority of oncogenic aberrations in spitzoid neoplasms and may serve as therapeutic targets for metastatic spitzoid melanoma.
- Thomas Wiesner
- , Jie He
- & Boris C. Bastian
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| Open AccessMaspin is not required for embryonic development or tumour suppression
A role for the serpin maspin has been described in both development and cancer. In this study, the authors demonstrate that maspin knockout mice develop normally and that maspin does not function as a tumour suppressor, suggesting that another gene at the maspin locus may be responsible for this activity.
- Sonia S. Y. Teoh
- , Jessica Vieusseux
- & Phillip I. Bird
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A dual role for autophagy in a murine model of lung cancer
Autophagy prolongs the survival of cells in stressful conditions but its role in cancer is unclear. Here, Rao et al. show that loss of the autophagic protein Atg5 enhanced cancer incidence but impaired tumour progression in a mouse model of lung cancer.
- Shuan Rao
- , Luigi Tortola
- & Josef M. Penninger
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Diversity-oriented synthesis as a tool for identifying new modulators of mitosis
Diversity-oriented synthesis is a useful tool to synthesize libraries of structurally complex molecules. Here, the authors show the utility of this method by ultimately identifying a compound causing mitotic arrest and cancer cell death.
- Brett M. Ibbeson
- , Luca Laraia
- & David R. Spring
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| Open AccessHeterogeneity of genomic evolution and mutational profiles in multiple myeloma
Multiple myeloma is a malignant plasma cell disorder with a complex molecular pathogenesis. Here, the authors perform whole-exome sequencing, copy-number profiling and cytogenetic analysis in 84 myeloma samples and highlight the diversity and evolution of the mutational profile underlying the disease.
- Niccolo Bolli
- , Hervé Avet-Loiseau
- & Nikhil C. Munshi
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| Open AccessThe pseudogene TUSC2P promotes TUSC2 function by binding multiple microRNAs
Non-coding RNAs have recently emerged as crucial regulators of gene expression. Here Rutnam et al.identify a pseudogene complementary to the 3′-UTR of the TUSC2 tumour suppressor that regulates TUSC2 levels by acting as a decoy for endogenous microRNAs and thereby inhibits tumorigenesis.
- Zina Jeyapalan Rutnam
- , William W. Du
- & Burton B. Yang
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| Open AccessmicroRNA-181a has a critical role in ovarian cancer progression through the regulation of the epithelial–mesenchymal transition
Ovarian cancer is often diagnosed at a late stage when metastasis has already occurred. In this study, Parikh et al.show that mir-181a is involved in mediating the epithelial-to-mesenchymal transition in ovarian cancer, leading to activation of the TGF-β signalling pathway and metastasis.
- Aditya Parikh
- , Christine Lee
- & Analisa DiFeo
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FOXL2 posttranslational modifications mediated by GSK3β determine the growth of granulosa cell tumours
The majority of ovarian granulosa tumours harbour the C134W mutation in FOXL2 but the mechanism of tumorigenesis is largely unknown. Here, Kim et al. show that mutant FOXL2 is hyperphosphorylated by GSK3β, which targets the protein for degradation, and find that GSK3β inhibition represses the growth of ovarian granulosa cells.
- Jae-Hong Kim
- , Yong-Hak Kim
- & Jeehyeon Bae
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Transcription factors FOXG1 and Groucho/TLE promote glioblastoma growth
Glioblastoma cancers contain brain tumour-initiating cells and targeting these specific cells is an attractive opportunity for therapy. In this study, the authors show that FOXG1 and Groucho/TLE transcription factors are important for glioblastoma growth and might be useful therapeutic targets.
- Federica Verginelli
- , Alessandro Perin
- & Stefano Stifani
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| Open AccessInactivation of the Hippo tumour suppressor pathway by integrin-linked kinase
The Hippo tumour suppressor pathway is inactivated in many cancer types, but how this occurs is unclear. Here, the authors show that integrin-linked kinase (ILK) has a role in inhibiting the Hippo pathway and pharmacological inhibition of ILK reduces the size of tumours in mice.
- Isabel Serrano
- , Paul C. McDonald
- & Shoukat Dedhar
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Spliced MDM2 isoforms promote mutant p53 accumulation and gain-of-function in tumorigenesis
Mdm2 controls the levels of the tumour suppressor p53 in cells and p53 is often mutated in cancer. Here, Zheng et al. show that a particular Mdm2 isoform that is altered in cancer leads to elevated levels of mutant p53 protein and enhanced gain-of-function of the protein.
- Tongsen Zheng
- , Jiabei Wang
- & Wenwei Hu
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Tumour-associated mutant p53 drives the Warburg effect
Many cancers harbour mutations in the tumour suppressor p53, which often then gains oncogenic functions. Here, the authors show that mutant p53 enhances glycolysis in tumour cells by promoting glucose uptake via a mechanism involving GLUT1, RhoA and ROCK.
- Cen Zhang
- , Juan Liu
- & Zhaohui Feng
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Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1
Insulinomas develop from pancreatic β-cells and secrete insulin, but the underlying genetic defects are largely unknown. In this study, Cao et al. identify recurrent T372R mutations in the transcription factor YY1, and validate this hotspot mutation in 30% of insulinomas.
- Yanan Cao
- , Zhibo Gao
- & Guang Ning
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| Open AccessMutational landscape of gingivo-buccal oral squamous cell carcinoma reveals new recurrently-mutated genes and molecular subgroups
Gingivo-buccal oral squamous cell carcinoma (OSCC-GB) is the leading cancer among males in India. Here, the authors carry out exome sequencing and recurrence testing in patients with OSCC-GB and highlight genes and biological pathways associated with the disease.
- Arindam Maitra
- , Nidhan K. Biswas
- & D. Sutradhar
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Cyclin D1 induction of Dicer governs microRNA processing and expression in breast cancer
Whether microRNA processing mediated by Dicer is regulated in a cell-cycle-dependent manner is unknown. Here, Chen et al.show that Cyclin D1, which is important in the control of the cell cycle, regulates the expression of Dicer, and that Cyclin D1 and Dicer expression levels correlate in breast cancer.
- Zuoren Yu
- , Liping Wang
- & Richard G. Pestell
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A common variant at 8q24.21 is associated with renal cell cancer
Renal cell carcinoma (RCC) accounts for 80–90% of all kidney cancers, but to date, only five genome-wide significant RCC risk loci have been identified. Here, Gudmundsson et al.identify a new RCC susceptibility locus and provide insight into the genetic basis of the disease.
- Julius Gudmundsson
- , Patrick Sulem
- & Kari Stefansson
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| Open AccessIdentification of a pan-cancer oncogenic microRNA superfamily anchored by a central core seed motif
AGO-CLIP permits the identification of miRNA target genes. Here, Hamilton et al. compile publicly available AGO-CLIP data and combine this information with miRNA analysis from The Cancer Genome Atlas, permitting the identification of an oncogenic miRNA superfamily that targets tumour suppressor genes.
- Mark P. Hamilton
- , Kimal Rajapakshe
- & Sean E. McGuire
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A Nodal-independent and tissue-intrinsic mechanism controls heart-looping chirality
Nodal signalling has been implicated in the asymmetric positioning of various organs. Here, Noël et al.show that the asymmetry of the embryonic zebrafish heart is also established in the absence of Nodal signalling, suggesting a Nodal-independent mechanism that relies on actomyosin activity.
- Emily S. Noël
- , Manon Verhoeven
- & Jeroen Bakkers
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Involvement of parental imprinting in the antisense regulation of onco-miR-372-373
The miR-372-3 cluster has a role in oncogenesis. In this study, by utilizing parthenogenetic induced pluripotent stem cells, that lack the paternal genome, Stelzer et al.report that these miR-372-3 are negatively regulated by a paternally imprinted antisense transcript and that loss of its expression promotes oncogenesis.
- Yonatan Stelzer
- , Ido Sagi
- & Nissim Benvenisty
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Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease
Selective targeting of cancer cells may improve therapeutic efficacy while reducing adverse effects. Here, Ueki et al.report selective activation of an anticancer drug upon removal of an acetylated lysine group by histone deacetylases and the tumour-associated protease cathepsin L.
- Nobuhide Ueki
- , Siyeon Lee
- & Michael J. Hayman
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ARF triggers senescence in Brca2-deficient cells by altering the spectrum of p53 transcriptional targets
The tumour suppressor ARF regulates p53 levels; however, in contrast to p53, ARF has not been implicated in the response to DNA damage. In this study, Carlos et al.show that single-stranded DNA formed in BRCA2-null cells triggers a DNA damage response leading to the activation of ARF and senescence.
- Ana Rita Carlos
- , Jose Miguel Escandell
- & Madalena Tarsounas
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Article
| Open AccessWnt secretion is required to maintain high levels of Wnt activity in colon cancer cells
Activating mutations in the Wnt signalling pathway are associated with colon cancer. Here the authors show that tumour cells carrying mutations in APC and β-catenin are still regulated by Wnt ligands, suggesting that Wnt secretion and receptor signalling remains important to control downstream signalling.
- Oksana Voloshanenko
- , Gerrit Erdmann
- & Michael Boutros
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Semiconductor-based DNA sequencing of histone modification states
Semiconductor-based, non-optical DNA sequencing technologies such as Ion Torrent sequencing offer speed and cost advantages compared with alternative techniques. Cheng et al. demonstrate a protocol allowing the use of Ion Torrent technology to sequence DNA from chromatin immunoprecipitation experiments.
- Christine S. Cheng
- , Kunal Rai
- & Ido Amit
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Article
| Open AccessDifferential regulation of the REGγ–proteasome pathway by p53/TGF-β signalling and mutant p53 in cancer cells
REGγ is a proteasome activator and is frequently overexpressed in cancer cells. Here Ali et al. demonstrate that p53/TGF-β signalling inhibits REGγ expression, whereas p53 mutations increase REGγ transcription, identifying a gain of function for mutant p53.
- Amjad Ali
- , Zhuo Wang
- & Xiaotao Li
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Article
| Open AccessHeterozygous mutations in PALB2 cause DNA replication and damage response defects
PALB2 is a BRCA1-/BRCA2-interacting protein and heterozygous mutations in PALB2 are associated with hereditary breast cancer predisposition. Here the authors show that human lymphoblastoid cells from heterozygous PALB2mutation carriers display abnormal DNA replication dynamics and DNA damage response.
- Jenni Nikkilä
- , Ann Christin Parplys
- & Robert Winqvist
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