Mismatch repair deficiency associated with overexpression of the MSH3 gene

[ { "id": "1700725", "title": "Next-generation characterization of the Cancer Cell Line Encyclopedia", "abstract": "Large panels of comprehensively characterized human cancer models, including the Cancer Cell Line Encyclopedia (CCLE), have provided a rigorous framework with which to study genetic variants, candidate targets, and small-molecule and biological therapeutics and to identify new marker-driven cancer dependencies. To improve our understanding of the molecular features that contribute to cancer phenotypes, including drug responses, here we have expanded the characterizations of cancer cell lines to include genetic, RNA splicing, DNA methylation, histone H3 modification, microRNA expression and reverse-phase protein array data for 1,072 cell lines from individuals of various lineages and ethnicities. Integration of these data with functional characterizations such as drug-sensitivity, short hairpin RNA knockdown and CRISPR–Cas9 knockout data reveals potential targets for cancer drugs and associated biomarkers. Together, this dataset and an accompanying public data portal provide a resource for the acceleration of cancer research using model cancer cell lines. The original Cancer Cell Line Encyclopedia (CCLE) is expanded with deeper characterization of over 1,000 cell lines, including genomic, transcriptomic, and proteomic data, and integration with drug-sensitivity and gene-dependency data.", "source_url": "https://www.nature.com/articles/s41586-019-1186-3", "doc_type": 4, "year": 2019, "issue": 7757, "volume": 569, "first_page": 503, "last_page": 508, "citation_count": 81, "reference_count": 26, "venue": { "id": 2110000195, "name": "NATURE", "abbr": "" }, "author": [ { "id": 1001165854, "name": "Mahmoud Ghandi" }, { "id": 1001496484, "name": "Franklin W. Huang" }, { "id": 1001172268, "name": "Judit Jané-Valbuena" }, { "id": 1001165855, "name": "Gregory V. Kryukov" }, { "id": 1001496485, "name": "Christopher C. Lo" }, { "id": 1001496486, "name": "E. Robert McDonald III" }, { "id": 1001165864, "name": "Jordi Barretina" }, { "id": 1001384357, "name": "Ellen T. Gelfand" }, { "id": 1001476421, "name": "Craig M. Bielski" }, { "id": 1000995980, "name": "Haoxin Li" }, { "id": 1001496487, "name": "Kevin Hu" }, { "id": 1001496488, "name": "Alexander Y. Andreev-Drakhlin" }, { "id": 1001182033, "name": "Jaegil Kim" }, { "id": 1001182021, "name": "Julian M. Hess" }, { "id": 1001161752, "name": "Brian J. Haas" }, { "id": 1001184741, "name": "Francois Aguet" }, { "id": 1001409587, "name": "Barbara A. Weir" }, { "id": 1001496489, "name": "Michael V. Rothberg" }, { "id": 1001457755, "name": "Brenton R. Paolella" }, { "id": 1001182038, "name": "Michael S. Lawrence" }, { "id": 1001184793, "name": "Rehan Akbani" }, { "id": 1001213111, "name": "Yiling Lu" }, { "id": 1001496490, "name": "Hong L. Tiv" }, { "id": 1001496491, "name": "Prafulla C. Gokhale" }, { "id": 1001496492, "name": "Antoine de Weck" }, { "id": 1001496493, "name": "Ali Amin Mansour" }, { "id": 1001496494, "name": "Coyin Oh" }, { "id": 1001312473, "name": "Juliann Shih" }, { "id": 1001496495, "name": "Kevin Hadi" }, { "id": 1001496496, "name": "Yanay Rosen" }, { "id": 1001496497, "name": "Jonathan Bistline" }, { "id": 1001165861, "name": "Kavitha Venkatesan" }, { "id": 1001172261, "name": "Anupama Reddy" }, { "id": 1001165859, "name": "Dmitriy Sonkin" }, { "id": 1001165858, "name": "Manway Liu" }, { "id": 1001165857, "name": "Joseph Lehár" }, { "id": 1001361501, "name": "Joshua M. Korn" }, { "id": 1001496498, "name": "Dale A. Porter" }, { "id": 1000260257, "name": "Michael D. Jones" }, { "id": 1001496499, "name": "Javad Golji" }, { "id": 1001165865, "name": "Giordano Caponigro" }, { "id": 1001496500, "name": "Jordan E. Taylor" }, { "id": 1001496501, "name": "Caitlin M. Dunning" }, { "id": 1001496502, "name": "Amanda L. Creech" }, { "id": 1001496503, "name": "Allison C. Warren" }, { "id": 1001164273, "name": "James M. McFarland" }, { "id": 1001496504, "name": "Mahdi Zamanighomi" }, { "id": 1001165860, "name": "Audrey Kauffmann" }, { "id": 1001165853, "name": "Nicolas Stransky" }, { "id": 1001255305, "name": "Marcin Imielinski" }, { "id": 1001182050, "name": "Yosef E. Maruvka" }, { "id": 1001184802, "name": "Andrew D. Cherniack" }, { "id": 1001164272, "name": "Aviad Tsherniak" }, { "id": 1001163954, "name": "Francisca Vazquez" }, { "id": 1001243440, "name": "Jacob D. Jaffe" }, { "id": 1001496505, "name": "Andrew A. Lane" }, { "id": 1001256376, "name": "David M. Weinstock" }, { "id": 1001496506, "name": "Cory M. Johannessen" }, { "id": 1001172305, "name": "Michael P. Morrissey" }, { "id": 1001165868, "name": "Frank Stegmeier" }, { "id": 1001165866, "name": "Robert Schlegel" }, { "id": 1001163955, "name": "William C. Hahn" }, { "id": 1001172293, "name": "Gad Getz" }, { "id": 1001184908, "name": "Gordon B. Mills" }, { "id": 1001164271, "name": "Jesse S. Boehm" }, { "id": 1001172304, "name": "Todd R. Golub" }, { "id": 1001165856, "name": "Levi A. Garraway" }, { "id": 1001165867, "name": "William R. Sellers" } ], "field": [ { "id": 2018252668, "name": "Penile cancer" }, { "id": 2017571735, "name": "Migrastatin" }, { "id": 2011716103, "name": "Halichondrin B" }, { "id": 2004556151, "name": "Appendix cancer" }, { "id": 2010169572, "name": "Mapatumumab" }, { "id": 2035334641, "name": "Grifola frondosa" }, { "id": 2048289856, "name": "Isomigrastatin" }, { "id": 2033698835, "name": "Lexatumumab" }, { "id": 2010034143, "name": "Drozitumab" }, { "id": 2038815967, "name": "Rhabdastrella globostellata" } ], "cite": [ { "name": "GB/T 7714", "text": "Ghandi Mahmoud, Huang Franklin W., Jané-Valbuena Judit, et al. Next-generation characterization of the Cancer Cell Line Encyclopedia[J]. NATURE, 2019, 569(7757): 503-508." }, { "name": "MLA", "text": "Ghandi, Mahmoud, et al. \"Next-generation characterization of the Cancer Cell Line Encyclopedia\" NATURE., vol. 569, no. 7757, 2019, pp. 503-508." }, { "name": "APA", "text": "Ghandi Mahmoud, Huang Franklin W., Jané-Valbuena Judit, Kryukov Gregory V., Lo Christopher C., III E. Robert McDonald, ... & Li Haoxin (2019). Next-generation characterization of the Cancer Cell Line Encyclopedia. NATURE, 569(7757), 503-508." }, { "name": "BibTeX", "text": "@inproceedings{Acemap1700725,\n title=\"Next-generation characterization of the Cancer Cell Line Encyclopedia\",\n author=\"Mahmoud {Ghandi} and {Franklin W. Huang} and {Judit Jané-Valbuena} and {Gregory V. Kryukov} and {Christopher C. Lo} and {E. Robert McDonald III} and Jordi {Barretina} and {Ellen T. Gelfand} and {Craig M. Bielski} and Haoxin {Li} and Kevin {Hu} and {Alexander Y. Andreev-Drakhlin} and Jaegil {Kim} and {Julian M. Hess} and {Brian J. Haas} and Francois {Aguet} and {Barbara A. Weir} and {Michael V. Rothberg} and {Brenton R. Paolella} and {Michael S. Lawrence} and Rehan {Akbani} and Yiling {Lu} and {Hong L. Tiv} and {Prafulla C. Gokhale} and Antoine de {Weck} and Ali Amin {Mansour} and Coyin {Oh} and Juliann {Shih} and Kevin {Hadi} and Yanay {Rosen} and Jonathan {Bistline} and Kavitha {Venkatesan} and Anupama {Reddy} and Dmitriy {Sonkin} and Manway {Liu} and {Joseph Lehár} and {Joshua M. Korn} and {Dale A. Porter} and {Michael D. Jones} and Javad {Golji} and Giordano {Caponigro} and {Jordan E. Taylor} and {Caitlin M. Dunning} and {Amanda L. Creech} and {Allison C. Warren} and {James M. McFarland} and Mahdi {Zamanighomi} and Audrey {Kauffmann} and Nicolas {Stransky} and Marcin {Imielinski} and {Yosef E. Maruvka} and {Andrew D. Cherniack} and Aviad {Tsherniak} and Francisca {Vazquez} and {Jacob D. Jaffe} and {Andrew A. Lane} and {David M. Weinstock} and {Cory M. Johannessen} and {Michael P. Morrissey} and Frank {Stegmeier} and Robert {Schlegel} and {William C. Hahn} and Gad {Getz} and {Gordon B. Mills} and {Jesse S. Boehm} and {Todd R. Golub} and {Levi A. Garraway} and {William R. Sellers}\",\n journal=\"NATURE\",\n volume=\"569\",\n number=\"7757\",\n pages=\"503--508\",\n url=\"https://www.acemap.info/paper/1700725\",\n year=\"2019\"\n}" } ] }, { "id": "2321788", "title": "ATR-Chk1 activation mitigates replication stress caused by mismatch repair-dependent processing of DNA damage", "abstract": "The mismatch repair pathway (MMR) is essential for removing DNA polymerase errors, thereby maintaining genomic stability. Loss of MMR function increases mutation frequency and is associated with tumorigenesis. However, how MMR is executed at active DNA replication forks is unclear. This has important implications for understanding how MMR repairs O6-methylguanine/thymidine (MeG/T) mismatches created upon exposure to DNA alkylating agents. If MeG/T lesion recognition by MMR initiates mismatch excision, the reinsertion of a mismatched thymidine during resynthesis could initiate futile repair cycles. One consequence of futile repair cycles might be a disruption of overall DNA replication in the affected cell. Herein, we show that in MMR-proficient HeLa cancer cells, treatment with a DNA alkylating agent slows S phase progression, yet cells still progress into the next cell cycle. In the first S phase following treatment, they activate ataxia telangiectasia and Rad3-related (ATR)-Checkpoint Kinase 1 (Chk1) signaling, which limits DNA damage, while inhibition of ATR kinase activity accelerates DNA damage accumulation and sensitivity to the DNA alkylating agent. We also observed that exposure of human embryonic stem cells to alkylation damage severely compromised DNA replication in a MMR-dependent manner. These cells fail to activate the ATR-Chk1 signaling axis, which may limit their ability to handle replication stress. Accordingly, they accumulate double-strand breaks and undergo immediate apoptosis. Our findings implicate the MMR-directed response to alkylation damage as a replication stress inducer, suggesting that repeated MMR processing of mismatches may occur that can disrupt S phase progression.", "source_url": "https://www.pnas.org/content/115/7/1523", "doc_type": 4, "year": 2018, "issue": 7, "volume": 115, "first_page": 1523, "last_page": 1528, "citation_count": 1, "reference_count": 2, "venue": { "id": 2110000201, "name": "PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA", "abbr": "" }, "author": [ { "id": 1001277459, "name": "Dipika Gupta" }, { "id": 1000341444, "name": "Bo Lin" }, { "id": 1001761630, "name": "Ann Cowan" }, { "id": 1001956712, "name": "Christopher D. Heinen" } ], "field": [ { "id": 2047856375, "name": "DNA gyrase" }, { "id": 2002788427, "name": "Pyrosequencing" }, { "id": 2046014516, "name": "Homoptera" }, { "id": 2015819948, "name": "Clorobiocin" } ], "cite": [ { "name": "GB/T 7714", "text": "Gupta Dipika, Lin Bo, Cowan Ann, et al. ATR-Chk1 activation mitigates replication stress caused by mismatch repair-dependent processing of DNA damage[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2018, 115(7): 1523-1528." }, { "name": "MLA", "text": "Gupta, Dipika, et al. \"ATR-Chk1 activation mitigates replication stress caused by mismatch repair-dependent processing of DNA damage\" PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA., vol. 115, no. 7, 2018, pp. 1523-1528." }, { "name": "APA", "text": "Gupta Dipika, Lin Bo, Cowan Ann, & Heinen Christopher D. (2018). ATR-Chk1 activation mitigates replication stress caused by mismatch repair-dependent processing of DNA damage. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 115(7), 1523-1528." }, { "name": "BibTeX", "text": "@inproceedings{Acemap2321788,\n title=\"ATR-Chk1 activation mitigates replication stress caused by mismatch repair-dependent processing of DNA damage\",\n author=\"Dipika {Gupta} and Bo {Lin} and Ann {Cowan} and {Christopher D. Heinen}\",\n journal=\"PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA\",\n volume=\"115\",\n number=\"7\",\n pages=\"1523--1528\",\n url=\"https://www.acemap.info/paper/2321788\",\n year=\"2018\"\n}" } ] }, { "id": "1880483", "title": "Overexpressed somatic alleles are enriched in functional elements in Breast Cancer", "abstract": "Asymmetric allele content in the transcriptome can be indicative of functional and selective features of the underlying genetic variants. Yet, imbalanced alleles, especially from diploid genome regions, are poorly explored in cancer. Here we systematically quantify and integrate the variant allele fraction from corresponding RNA and DNA sequence data from patients with breast cancer acquired through The Cancer Genome Atlas (TCGA). We test for correlation between allele prevalence and functionality in known cancer-implicated genes from the Cancer Gene Census (CGC). We document significant allele-preferential expression of functional variants in CGC genes and across the entire dataset. Notably, we find frequent allele-specific overexpression of variants in tumor-suppressor genes. We also report a list of over-expressed variants from non-CGC genes. Overall, our analysis presents an integrated set of features of somatic allele expression and points to the vast information content of the asymmetric alleles in the cancer transcriptome.", "source_url": "https://www.nature.com/articles/s41598-017-08416-w", "doc_type": 4, "year": 2017, "issue": 1, "volume": 7, "first_page": 1, "last_page": 10, "citation_count": 1, "reference_count": 12, "venue": { "id": 2110000208, "name": "SCIENTIFIC REPORTS", "abbr": "" }, "author": [ { "id": 1001486676, "name": "Paula Restrepo" }, { "id": 1001639041, "name": "Mercedeh Movassagh" }, { "id": 1001639040, "name": "Nawaf Alomran" }, { "id": 1001777666, "name": "Christian Miller" }, { "id": 1001380534, "name": "Muzi Li" }, { "id": 1001639042, "name": "Chris Trenkov" }, { "id": 1001777667, "name": "Yulian Manchev" }, { "id": 1001777668, "name": "Sonali Bahl" }, { "id": 1001777669, "name": "Stephanie Warnken" }, { "id": 1001639039, "name": "Liam Spurr" }, { "id": 1001639044, "name": "Tatiyana Apanasovich" }, { "id": 1001777670, "name": "Keith Crandall" }, { "id": 1001639045, "name": "Nathan Edwards" }, { "id": 1001584039, "name": "Anelia Horvath" } ], "field": [ { "id": 2018252668, "name": "Penile cancer" }, { "id": 2017571735, "name": "Migrastatin" }, { "id": 2011716103, "name": "Halichondrin B" }, { "id": 2004556151, "name": "Appendix cancer" } ], "cite": [ { "name": "GB/T 7714", "text": "Restrepo Paula, Movassagh Mercedeh, Alomran Nawaf, et al. Overexpressed somatic alleles are enriched in functional elements in Breast Cancer[J]. SCIENTIFIC REPORTS, 2017, 7(1): 1-10." }, { "name": "MLA", "text": "Restrepo, Paula, et al. \"Overexpressed somatic alleles are enriched in functional elements in Breast Cancer\" SCIENTIFIC REPORTS., vol. 7, no. 1, 2017, pp. 1-10." }, { "name": "APA", "text": "Restrepo Paula, Movassagh Mercedeh, Alomran Nawaf, Miller Christian, Li Muzi, Trenkov Chris, ... & Spurr Liam (2017). Overexpressed somatic alleles are enriched in functional elements in Breast Cancer. SCIENTIFIC REPORTS, 7(1), 1-10." }, { "name": "BibTeX", "text": "@inproceedings{Acemap1880483,\n title=\"Overexpressed somatic alleles are enriched in functional elements in Breast Cancer\",\n author=\"Paula {Restrepo} and Mercedeh {Movassagh} and Nawaf {Alomran} and Christian {Miller} and Muzi {Li} and Chris {Trenkov} and Yulian {Manchev} and Sonali {Bahl} and Stephanie {Warnken} and Liam {Spurr} and Tatiyana {Apanasovich} and Keith {Crandall} and Nathan {Edwards} and Anelia {Horvath}\",\n journal=\"SCIENTIFIC REPORTS\",\n volume=\"7\",\n number=\"1\",\n pages=\"1--10\",\n url=\"https://www.acemap.info/paper/1880483\",\n year=\"2017\"\n}" } ] }, { "id": "3249190", "title": "Novel Implications in Molecular Diagnosis of Lynch Syndrome", "abstract": "About 10% of total colorectal cancers are associated with known Mendelian inheritance, as Familial Adenomatous Polyposis (FAP) and Lynch syndrome (LS). In these cancer types the clinical manifestations of disease are due to mutations in high-risk alleles, with a penetrance at least of 70%. The LS is associated with germline mutations in the DNA mismatch repair (MMR) genes. However, the mutation detection analysis of these genes does not always provide informative results for genetic counseling of LS patients. Very often, the molecular analysis reveals the presence of variants of unknown significance (VUSs) whose interpretation is not easy and requires the combination of different analytical strategies to get a proper assessment of their pathogenicity. In some cases, these VUSs may make a more substantial overall contribution to cancer risk than the well-assessed severe Mendelian variants. Moreover, it could also be possible that the simultaneous presence of these genetic variants in several MMR genes that behave as low risk alleles might contribute in a cooperative manner to increase the risk of hereditary cancer. In this paper, through a review of the recent literature, we have speculated a novel inheritance model in the Lynch syndrome; this could pave the way toward new diagnostic perspectives.", "source_url": "https://www.hindawi.com/journals/grp/2017/2595098/", "doc_type": 4, "year": 2017, "issue": 0, "volume": 2017, "first_page": 0, "last_page": 0, "citation_count": 1, "reference_count": 13, "venue": { "id": 2110000438, "name": "GASTROENTEROLOGY RESEARCH AND PRACTICE", "abbr": "" }, "author": [ { "id": 1003423881, "name": "Liccardo, Raffaella" }, { "id": 1003160089, "name": "De Rosa, Marina" }, { "id": 1003160094, "name": "Paola Izzo" }, { "id": 1003423882, "name": "Duraturo, Francesca" } ], "field": [ { "id": 2018252668, "name": "Penile cancer" }, { "id": 2022723334, "name": "Rapunzel syndrome" }, { "id": 2009106970, "name": "Oculocerebral-hypopigmentation syndrome" }, { "id": 2010169572, "name": "Mapatumumab" } ], "cite": [ { "name": "GB/T 7714", "text": "Raffaella Liccardo,, Marina De Rosa,, Izzo Paola, et al. Novel Implications in Molecular Diagnosis of Lynch Syndrome[J]. GASTROENTEROLOGY RESEARCH AND PRACTICE, 2017, 2017." }, { "name": "MLA", "text": "Raffaella, Liccardo,, et al. \"Novel Implications in Molecular Diagnosis of Lynch Syndrome\" GASTROENTEROLOGY RESEARCH AND PRACTICE., vol. 2017, 2017." }, { "name": "APA", "text": "Raffaella Liccardo,, Marina De Rosa,, Izzo Paola, & Francesca Duraturo, (2017). Novel Implications in Molecular Diagnosis of Lynch Syndrome. GASTROENTEROLOGY RESEARCH AND PRACTICE, 2017." }, { "name": "BibTeX", "text": "@inproceedings{Acemap3249190,\n title=\"Novel Implications in Molecular Diagnosis of Lynch Syndrome\",\n author=\"{Liccardo, Raffaella} and {De Rosa, Marina} and Paola {Izzo} and {Duraturo, Francesca}\",\n journal=\"GASTROENTEROLOGY RESEARCH AND PRACTICE\",\n volume=\"2017\",\n url=\"https://www.acemap.info/paper/3249190\",\n year=\"2017\"\n}" } ] }, { "id": "1656285", "title": "NEK1 kinase domain structure and its dynamic protein interactome after exposure to Cisplatin", "abstract": "NEK family kinases are serine/threonine kinases that have been functionally implicated in the regulation of the disjunction of the centrosome, the assembly of the mitotic spindle, the function of the primary cilium and the DNA damage response. NEK1 shows pleiotropic functions and has been found to be mutated in cancer cells, ciliopathies such as the polycystic kidney disease, as well as in the genetic diseases short-rib thoracic dysplasia, Mohr-syndrome and amyotrophic lateral sclerosis. NEK1 is essential for the ionizing radiation DNA damage response and priming of the ATR kinase and of Rad54 through phosphorylation. Here we report on the structure of the kinase domain of human NEK1 in its apo- and ATP-mimetic inhibitor bound forms. The inhibitor bound structure may allow the design of NEK specific chemo-sensitizing agents to act in conjunction with chemo- or radiation therapy of cancer cells. Furthermore, we characterized the dynamic protein interactome of NEK1 after DNA damage challenge with cisplatin. Our data suggest that NEK1 and its interaction partners trigger the DNA damage pathways responsible for correcting DNA crosslinks.", "source_url": "https://www.nature.com/articles/s41598-017-05325-w", "doc_type": 4, "year": 2017, "issue": 1, "volume": 7, "first_page": 1, "last_page": 13, "citation_count": 0, "reference_count": 9, "venue": { "id": 2110000208, "name": "SCIENTIFIC REPORTS", "abbr": "" }, "author": [ { "id": 1001413784, "name": "Talita D. Melo-Hanchuk" }, { "id": 1001413785, "name": "Priscila Ferreira Slepicka" }, { "id": 1001413786, "name": "Gabriela Vaz Meirelles" }, { "id": 1001413787, "name": "Fernanda Luisa Basei" }, { "id": 1001413788, "name": "Diogo Ventura Lovato" }, { "id": 1001413789, "name": "Daniela Campos Granato" }, { "id": 1001413790, "name": "Bianca Alves Pauletti" }, { "id": 1001413791, "name": "Romenia Ramos Domingues" }, { "id": 1001252026, "name": "Adriana Franco Paes Leme" }, { "id": 1001413792, "name": "Alessandra Luiza Pelegrini" }, { "id": 1001413793, "name": "Guido Lenz" }, { "id": 1001413794, "name": "Stefan Knapp" }, { "id": 1001368123, "name": "Jonathan M. Elkins" }, { "id": 1001247021, "name": "Jörg Kobarg" } ], "field": [ { "id": 2047856375, "name": "DNA gyrase" }, { "id": 2039056458, "name": "Ungiminorine" } ], "cite": [ { "name": "GB/T 7714", "text": "Melo-Hanchuk Talita D., Slepicka Priscila Ferreira, Meirelles Gabriela Vaz, et al. NEK1 kinase domain structure and its dynamic protein interactome after exposure to Cisplatin[J]. SCIENTIFIC REPORTS, 2017, 7(1): 1-13." }, { "name": "MLA", "text": "Melo-Hanchuk, Talita D., et al. \"NEK1 kinase domain structure and its dynamic protein interactome after exposure to Cisplatin\" SCIENTIFIC REPORTS., vol. 7, no. 1, 2017, pp. 1-13." }, { "name": "APA", "text": "Melo-Hanchuk Talita D., Slepicka Priscila Ferreira, Meirelles Gabriela Vaz, Basei Fernanda Luisa, Lovato Diogo Ventura, Granato Daniela Campos, ... & Pelegrini Alessandra Luiza (2017). NEK1 kinase domain structure and its dynamic protein interactome after exposure to Cisplatin. SCIENTIFIC REPORTS, 7(1), 1-13." }, { "name": "BibTeX", "text": "@inproceedings{Acemap1656285,\n title=\"NEK1 kinase domain structure and its dynamic protein interactome after exposure to Cisplatin\",\n author=\"{Talita D. Melo-Hanchuk} and Priscila Ferreira {Slepicka} and Gabriela Vaz {Meirelles} and Fernanda Luisa {Basei} and Diogo Ventura {Lovato} and Daniela Campos {Granato} and Bianca Alves {Pauletti} and Romenia Ramos {Domingues} and Adriana Franco Paes {Leme} and Alessandra Luiza {Pelegrini} and Guido {Lenz} and Stefan {Knapp} and {Jonathan M. Elkins} and {Jörg Kobarg}\",\n journal=\"SCIENTIFIC REPORTS\",\n volume=\"7\",\n number=\"1\",\n pages=\"1--13\",\n url=\"https://www.acemap.info/paper/1656285\",\n year=\"2017\"\n}" } ] }, { "id": "3684782", "title": "MSH3-Deficiency Initiates EMAST without Oncogenic Transformation of Human Colon Epithelial Cells", "abstract": "Background/Aim Elevated microsatellite instability at selected tetranucleotide repeats (EMAST) is a genetic signature in certain cases of sporadic colorectal cancer and has been linked to MSH3-deficiency. It is currently controversial whether EMAST is associated with oncogenic properties in humans, specifically as cancer development in Msh3-deficient mice is not enhanced. However, a mutator phenotype is different between species as the genetic positions of repetitive sequences are not conserved. Here we studied the molecular effects of human MSH3-deficiency. Methods HCT116 and HCT116+chr3 (both MSH3-deficient) and primary human colon epithelial cells (HCEC, MSH3-wildtype) were stably transfected with an EGFP-based reporter plasmid for the detection of frameshift mutations within an [AAAG]17 repeat. MSH3 was silenced by shRNA and changes in protein expression were analyzed by shotgun proteomics. Colony forming assay was used to determine oncogenic transformation and double strand breaks (DSBs) were assessed by Comet assay. Results Despite differential MLH1 expression, both HCT116 and HCT116+chr3 cells displayed comparable high mutation rates (about 4×10−4) at [AAAG]17 repeats. Silencing of MSH3 in HCECs leads to a remarkable increased frameshift mutations in [AAAG]17 repeats whereas [CA]13 repeats were less affected. Upon MSH3-silencing, significant changes in the expression of 202 proteins were detected. Pathway analysis revealed overexpression of proteins involved in double strand break repair (MRE11 and RAD50), apoptosis, L1 recycling, and repression of proteins involved in metabolism, tRNA aminoacylation, and gene expression. MSH3-silencing did not induce oncogenic transformation and DSBs increased 2-fold. Conclusions MSH3-deficiency in human colon epithelial cells results in EMAST, formation of DSBs and significant changes of the proteome but lacks oncogenic transformation. Thus, MSH3-deficiency alone is unlikely to drive human colon carcinogenesis.", "source_url": "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050541", "doc_type": 4, "year": 2012, "issue": 11, "volume": 7, "first_page": 0, "last_page": 0, "citation_count": 10, "reference_count": 11, "venue": { "id": 2110000215, "name": "PLOS ONE", "abbr": "" }, "author": [ { "id": 1003146807, "name": "Christoph Campregher" }, { "id": 1003879647, "name": "Gerald Schmid" }, { "id": 1002191911, "name": "Franziska Ferk" }, { "id": 1002146785, "name": "Siegfried Knasmüller" }, { "id": 1001328629, "name": "Vineeta Khare" }, { "id": 1002070980, "name": "Benedikt Kortüm" }, { "id": 1003346785, "name": "Kyle Dammann" }, { "id": 1001328635, "name": "Michaela Lang" }, { "id": 1003848857, "name": "Theresa Scharl" }, { "id": 1001179940, "name": "Andreas Spittler" }, { "id": 1003227275, "name": "Andres I. Roig" }, { "id": 1001491682, "name": "Jerry W. Shay" }, { "id": 1001238264, "name": "Christopher Gerner" }, { "id": 1001328637, "name": "Christoph Gasche" } ], "field": [ { "id": 2047317996, "name": "Cecum" } ], "cite": [ { "name": "GB/T 7714", "text": "Campregher Christoph, Schmid Gerald, Ferk Franziska, et al. MSH3-Deficiency Initiates EMAST without Oncogenic Transformation of Human Colon Epithelial Cells[J]. PLOS ONE, 2012, 7(11)." }, { "name": "MLA", "text": "Campregher, Christoph, et al. \"MSH3-Deficiency Initiates EMAST without Oncogenic Transformation of Human Colon Epithelial Cells\" PLOS ONE., vol. 7, no. 11, 2012." }, { "name": "APA", "text": "Campregher Christoph, Schmid Gerald, Ferk Franziska, Knasmüller Siegfried, Khare Vineeta, Kortüm Benedikt, ... & Spittler Andreas (2012). MSH3-Deficiency Initiates EMAST without Oncogenic Transformation of Human Colon Epithelial Cells. PLOS ONE, 7(11)." }, { "name": "BibTeX", "text": "@inproceedings{Acemap3684782,\n title=\"MSH3-Deficiency Initiates EMAST without Oncogenic Transformation of Human Colon Epithelial Cells\",\n author=\"Christoph {Campregher} and Gerald {Schmid} and Franziska {Ferk} and {Siegfried Knasmüller} and Vineeta {Khare} and {Benedikt Kortüm} and Kyle {Dammann} and Michaela {Lang} and Theresa {Scharl} and Andreas {Spittler} and {Andres I. Roig} and {Jerry W. Shay} and Christopher {Gerner} and Christoph {Gasche}\",\n journal=\"PLOS ONE\",\n volume=\"7\",\n number=\"11\",\n url=\"https://www.acemap.info/paper/3684782\",\n year=\"2012\"\n}" } ] }, { "id": "2380161", "title": "Interplay between mismatch repair and chromatin assembly", "abstract": "Single strand nicks and gaps in DNA have been reported to increase the efficiency of nucleosome loading mediated by chromatin assembly factor 1 (CAF-1). However, on mismatch-containing substrates, these strand discontinuities are utilized by the mismatch repair (MMR) system as loading sites for exonuclease 1, at which degradation of the error-containing strand commences. Because packaging of DNA into chromatin might inhibit MMR, we were interested to learn whether chromatin assembly is differentially regulated on heteroduplex and homoduplex substrates. We now show that the presence of a mismatch in a nicked plasmid substrate delays nucleosome loading in human cell extracts. Our data also suggest that, once the mismatch is removed, repair of the single-stranded gap is accompanied by efficient nucleosome loading. We postulated that the balance between MMR and chromatin assembly might be governed by proliferating cell nuclear antigen (PCNA), the processivity factor of replicative DNA polymerases, which is loaded at DNA termini and which interacts with the MSH6 subunit of the mismatch recognition factor MutSα, as well as with CAF-1. We now show that this regulation might be more complex; MutSα and CAF-1 interact not only with PCNA, but also with each other. In vivo this interaction increases during S-phase and may be controlled by the phosphorylation status of the p150 subunit of CAF-1.", "source_url": "https://www.pnas.org/content/109/6/1895", "doc_type": 4, "year": 2012, "issue": 6, "volume": 109, "first_page": 1895, "last_page": 1900, "citation_count": 6, "reference_count": 3, "venue": { "id": 2110000201, "name": "PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA", "abbr": "" }, "author": [ { "id": 1002612378, "name": "Barbara Schöpf" }, { "id": 1002612379, "name": "Stephanie Bregenhorn" }, { "id": 1001207751, "name": "Jean-Pierre Quivy" }, { "id": 1002527410, "name": "Farid A. Kadyrov" }, { "id": 1001207752, "name": "Geneviève Almouzni" }, { "id": 1001168069, "name": "Josef Jiricny" } ], "field": [ { "id": 2047856375, "name": "DNA gyrase" } ], "cite": [ { "name": "GB/T 7714", "text": "Schöpf Barbara, Bregenhorn Stephanie, Quivy Jean-Pierre, et al. Interplay between mismatch repair and chromatin assembly[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2012, 109(6): 1895-1900." }, { "name": "MLA", "text": "Schöpf, Barbara, et al. \"Interplay between mismatch repair and chromatin assembly\" PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA., vol. 109, no. 6, 2012, pp. 1895-1900." }, { "name": "APA", "text": "Schöpf Barbara, Bregenhorn Stephanie, Quivy Jean-Pierre, Kadyrov Farid A., Almouzni Geneviève, & Jiricny Josef (2012). Interplay between mismatch repair and chromatin assembly. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 109(6), 1895-1900." }, { "name": "BibTeX", "text": "@inproceedings{Acemap2380161,\n title=\"Interplay between mismatch repair and chromatin assembly\",\n author=\"{Barbara Schöpf} and Stephanie {Bregenhorn} and {Jean-Pierre Quivy} and {Farid A. Kadyrov} and {Geneviève Almouzni} and Josef {Jiricny}\",\n journal=\"PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA\",\n volume=\"109\",\n number=\"6\",\n pages=\"1895--1900\",\n url=\"https://www.acemap.info/paper/2380161\",\n year=\"2012\"\n}" } ] }, { "id": "2312940", "title": "Isolated short CTG/CAG DNA slip-outs are repaired efficiently by hMutSβ, but clustered slip-outs are poorly repaired", "abstract": "Expansions of CTG/CAG trinucleotide repeats, thought to involve slipped DNAs at the repeats, cause numerous diseases including myotonic dystrophy and Huntington's disease. By unknown mechanisms, further repeat expansions in transgenic mice carrying expanded CTG/CAG tracts require the mismatch repair (MMR) proteins MSH2 and MSH3, forming the MutSβ complex. Using an in vitro repair assay, we investigated the effect of slip-out size, with lengths of 1, 3, or 20 excess CTG repeats, as well as the effect of the number of slip-outs per molecule, on the requirement for human MMR. Long slip-outs escaped repair, whereas short slip-outs were repaired efficiently, much greater than a G-T mismatch, but required hMutSβ. Higher or lower levels of hMutSβ or its complete absence were detrimental to proper repair of short slip-outs. Surprisingly, clusters of as many as 62 short slip-outs (one to three repeat units each) along a single DNA molecule with (CTG)50•(CAG)50 repeats were refractory to repair, and repair efficiency was reduced further without MMR. Consistent with the MutSβ requirement for instability, hMutSβ is required to process isolated short slip-outs; however, multiple adjacent short slip-outs block each other's repair, possibly acting as roadblocks to progression of repair and allowing error-prone repair. Results suggest that expansions can arise by escaped repair of long slip-outs, tandem short slip-outs, or isolated short slip-outs; the latter two types are sensitive to hMutSβ. Poor repair of clustered DNA lesions has previously been associated only with ionizing radiation damage. Our results extend this interference in repair to neurodegenerative disease-causing mutations in which clustered slip-outs escape proper repair and lead to expansions.", "source_url": "https://www.pnas.org/content/107/28/12593", "doc_type": 4, "year": 2010, "issue": 28, "volume": 107, "first_page": 12593, "last_page": 12598, "citation_count": 4, "reference_count": 7, "venue": { "id": 2110000201, "name": "PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA", "abbr": "" }, "author": [ { "id": 1002505553, "name": "Gagan B. Panigrahi" }, { "id": 1002505554, "name": "Meghan M. Slean" }, { "id": 1002505555, "name": "Jodie P. Simard" }, { "id": 1001368125, "name": "Opher Gileadi" }, { "id": 1001803224, "name": "Christopher E. Pearson" } ], "field": [], "cite": [ { "name": "GB/T 7714", "text": "Panigrahi Gagan B., Slean Meghan M., Simard Jodie P., et al. Isolated short CTG/CAG DNA slip-outs are repaired efficiently by hMutSβ, but clustered slip-outs are poorly repaired[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107(28): 12593-12598." }, { "name": "MLA", "text": "Panigrahi, Gagan B., et al. \"Isolated short CTG/CAG DNA slip-outs are repaired efficiently by hMutSβ, but clustered slip-outs are poorly repaired\" PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA., vol. 107, no. 28, 2010, pp. 12593-12598." }, { "name": "APA", "text": "Panigrahi Gagan B., Slean Meghan M., Simard Jodie P., Gileadi Opher, & Pearson Christopher E. (2010). Isolated short CTG/CAG DNA slip-outs are repaired efficiently by hMutSβ, but clustered slip-outs are poorly repaired. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 107(28), 12593-12598." }, { "name": "BibTeX", "text": "@inproceedings{Acemap2312940,\n title=\"Isolated short CTG/CAG DNA slip-outs are repaired efficiently by hMutSβ, but clustered slip-outs are poorly repaired\",\n author=\"{Gagan B. Panigrahi} and {Meghan M. Slean} and {Jodie P. Simard} and Opher {Gileadi} and {Christopher E. Pearson}\",\n journal=\"PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA\",\n volume=\"107\",\n number=\"28\",\n pages=\"12593--12598\",\n url=\"https://www.acemap.info/paper/2312940\",\n year=\"2010\"\n}" } ] }, { "id": "3218707", "title": "Pathogenicity of MSH2 Missense Mutations Is Typically Associated With Impaired Repair Capability of the Mutated Protein", "abstract": "Inherited deleterious mutations in mismatch repair genes , , and predispose to hereditary nonpolyposis colorectal cancer. A major diagnostic challenge is the difficulty in evaluating the pathogenicity of missense mutations. Previously we showed that most missense variants in do not impair MMR capability and are associated with no or low cancer susceptibility, whereas in , functional studies distinguished nontruncating mutations with severe defects from those not or slightly impaired in protein expression or function. The present study was undertaken to evaluate the pathogenicity of inherited missense mutations in . Fifteen mutated MSH2 proteins including 14 amino acid substitutions and one in-frame deletion were tested for expression/stability, MSH2/MSH6 interaction, and repair efficiency. The genetic and biochemical data were correlated with the clinical data. Comparative sequence analysis was performed to assess the value of sequence homology as a tool for predicting functional results. None of the studied mutations destroyed the protein or abolished MSH2/MSH6 interaction, whereas 12 mutations impaired the repair capability of the protein. Comparative sequence analysis correctly predicted functional studies for 13 of 14 amino acid substitutions. Interpretation was pathogenic for 12, nonpathogenic for 2, and contradictory for 1 mutation. The pathogenicity could not be distinguished unambiguously by phenotypic characteristics, although correlation between the absence of staining for MSH2 and pathogenicity of the missense mutation was notable. Unlike in and , the pathogenicity of missense mutations in was always associated with impaired repair capability of the mutated protein.", "source_url": "https://www.sciencedirect.com/science/article/abs/pii/S001650850601804X", "doc_type": 4, "year": 2006, "issue": 5, "volume": 131, "first_page": 1408, "last_page": 1417, "citation_count": 4, "reference_count": 9, "venue": { "id": 2110000444, "name": "GASTROENTEROLOGY", "abbr": "" }, "author": [ { "id": 1001727884, "name": "Saara Ollila" }, { "id": 1003396992, "name": "Laura Sarantaus" }, { "id": 1003396993, "name": "Reetta Kariola" }, { "id": 1003373203, "name": "Philip Chan" }, { "id": 1001974231, "name": "Heather Hampel" }, { "id": 1001951502, "name": "Elke Holinski-Feder" }, { "id": 1001626031, "name": "Finlay Macrae" }, { "id": 1001811117, "name": "Maija Kohonen-Corish" }, { "id": 1001977433, "name": "Anne-Marie Gerdes" }, { "id": 1002578198, "name": "Päivi Peltomäki" }, { "id": 1001486741, "name": "Elisabeth Mangold" }, { "id": 1001276061, "name": "Albert de la Chapelle" }, { "id": 1003361120, "name": "Marc Greenblatt" }, { "id": 1003361121, "name": "Minna Nyström" } ], "field": [], "cite": [ { "name": "GB/T 7714", "text": "Ollila Saara, Sarantaus Laura, Kariola Reetta, et al. Pathogenicity of MSH2 Missense Mutations Is Typically Associated With Impaired Repair Capability of the Mutated Protein[J]. GASTROENTEROLOGY, 2006, 131(5): 1408-1417." }, { "name": "MLA", "text": "Ollila, Saara, et al. \"Pathogenicity of MSH2 Missense Mutations Is Typically Associated With Impaired Repair Capability of the Mutated Protein\" GASTROENTEROLOGY., vol. 131, no. 5, 2006, pp. 1408-1417." }, { "name": "APA", "text": "Ollila Saara, Sarantaus Laura, Kariola Reetta, Chan Philip, Hampel Heather, Holinski-Feder Elke, ... & Peltomäki Päivi (2006). Pathogenicity of MSH2 Missense Mutations Is Typically Associated With Impaired Repair Capability of the Mutated Protein. GASTROENTEROLOGY, 131(5), 1408-1417." }, { "name": "BibTeX", "text": "@inproceedings{Acemap3218707,\n title=\"Pathogenicity of MSH2 Missense Mutations Is Typically Associated With Impaired Repair Capability of the Mutated Protein\",\n author=\"Saara {Ollila} and Laura {Sarantaus} and Reetta {Kariola} and Philip {Chan} and Heather {Hampel} and {Elke Holinski-Feder} and Finlay {Macrae} and {Maija Kohonen-Corish} and {Anne-Marie Gerdes} and {Päivi Peltomäki} and Elisabeth {Mangold} and Albert de la {Chapelle} and Marc {Greenblatt} and {Minna Nyström}\",\n journal=\"GASTROENTEROLOGY\",\n volume=\"131\",\n number=\"5\",\n pages=\"1408--1417\",\n url=\"https://www.acemap.info/paper/3218707\",\n year=\"2006\"\n}" } ] }, { "id": "3034093", "title": "Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system", "abstract": "Germline mutations in the DNA mismatch repair (MMR) genes and are associated with susceptibility to hereditary nonpolyposis colorectal cancer (HNPCC). Because a significant proportion of mutations are missense, the assessment of their pathogenic role may be difficult. To date, functional analysis of missense mutations has been performed primarily in . The aim of this study was to examine the biochemical properties of hMLH1 protein variants in a human expression system. The HNPCC-related mutations T117M, V185G, R217C, G244D, R265C, V326A, and K618T, the polymorphisms I219V and R265H, and a splicing variant lacking exon 9 and 10 (hMLH1▵9/10) were cloned. On transfection of these constructs into human 293T cells, which do not express hMLH1 because of promoter hypermethylation, the hMLH1 protein variants were analyzed by Western blotting and in a MMR assay. Transfection was successful for all constructs. As anticipated, the mutations K618T and T117M, which affect the highly conserved domains of hMLH1 that are necessary for interaction with hPMS2 or for adenosine triphosphate (ATP) binding, respectively, affected protein stability or its ability to complement MMR-deficient 293T-cell extracts. The V185G, G244D, and ▵9/10 variants were also unable to complement MMR in 293T cells, whereas hMLH1 proteins carrying the I219V, R265H, R265C, R217C, and V326A mutations were MMR competent. These data show that the pathogenic role of missense mutations and splicing variants can be assessed by analyzing the biochemical properties of their protein products in a homologous expression system.GASTROENTEROLOGY 2002;122:211-219", "source_url": "https://www.sciencedirect.com/science/article/pii/S0016508502075790", "doc_type": 4, "year": 2002, "issue": 1, "volume": 122, "first_page": 211, "last_page": 219, "citation_count": 14, "reference_count": 15, "venue": { "id": 2110000444, "name": "GASTROENTEROLOGY", "abbr": "" }, "author": [ { "id": 1003119741, "name": "Joerg Trojan" }, { "id": 1001221702, "name": "Stefan Zeuzem" }, { "id": 1003068051, "name": "Ann Randolph" }, { "id": 1003197205, "name": "Christine Hemmerle" }, { "id": 1001221701, "name": "Angela Brieger" }, { "id": 1002191513, "name": "Jochen Raedle" }, { "id": 1001221703, "name": "Guido Plotz" }, { "id": 1001168069, "name": "Josef Jiricny" }, { "id": 1001800250, "name": "Giancarlo Marra" } ], "field": [], "cite": [ { "name": "GB/T 7714", "text": "Trojan Joerg, Zeuzem Stefan, Randolph Ann, et al. Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system[J]. GASTROENTEROLOGY, 2002, 122(1): 211-219." }, { "name": "MLA", "text": "Trojan, Joerg, et al. \"Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system\" GASTROENTEROLOGY., vol. 122, no. 1, 2002, pp. 211-219." }, { "name": "APA", "text": "Trojan Joerg, Zeuzem Stefan, Randolph Ann, Hemmerle Christine, Brieger Angela, Raedle Jochen, ... & Marra Giancarlo (2002). Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system. GASTROENTEROLOGY, 122(1), 211-219." }, { "name": "BibTeX", "text": "@inproceedings{Acemap3034093,\n title=\"Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system\",\n author=\"Joerg {Trojan} and Stefan {Zeuzem} and Ann {Randolph} and Christine {Hemmerle} and Angela {Brieger} and Jochen {Raedle} and Guido {Plotz} and Josef {Jiricny} and Giancarlo {Marra}\",\n journal=\"GASTROENTEROLOGY\",\n volume=\"122\",\n number=\"1\",\n pages=\"211--219\",\n url=\"https://www.acemap.info/paper/3034093\",\n year=\"2002\"\n}" } ] } ]