BRCA1 mislocalization leads to aberrant DNA damage response in heterozygous ABRAXAS1 mutation carrier cells

  1. Bose, Muthiah
  2. Sachsenweger, Juliane
  3. Laurila, Niina
  4. Parplys, Ann Christin
  5. Willmann, Jonas
  6. Jungwirth, Johannes
  7. Groth, Marco
  8. Rapakko, Katrin
  9. Nieminen, Pentti
  10. Friedl, Thomas W P
  11. Heiserich, Lisa
  12. Meyer, Felix
  13. Tuppurainen, Hanna
  14. Peltoketo, Hellevi
  15. Nevanlinna, Heli
  16. Pylkäs, Katri
  17. Borgmann, Kerstin
  18. Wiesmüller, Lisa
  19. Winqvist, Robert
  20. Pospiech, Helmut

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WeightNameValue
1000 Titel
  • BRCA1 mislocalization leads to aberrant DNA damage response in heterozygous ABRAXAS1 mutation carrier cells
1000 Autor/in
  1. Bose, Muthiah |
  2. Sachsenweger, Juliane |
  3. Laurila, Niina |
  4. Parplys, Ann Christin |
  5. Willmann, Jonas |
  6. Jungwirth, Johannes |
  7. Groth, Marco |
  8. Rapakko, Katrin |
  9. Nieminen, Pentti |
  10. Friedl, Thomas W P |
  11. Heiserich, Lisa |
  12. Meyer, Felix |
  13. Tuppurainen, Hanna |
  14. Peltoketo, Hellevi |
  15. Nevanlinna, Heli |
  16. Pylkäs, Katri |
  17. Borgmann, Kerstin |
  18. Wiesmüller, Lisa |
  19. Winqvist, Robert |
  20. Pospiech, Helmut |
1000 Erscheinungsjahr 2019
1000 LeibnizOpen
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2019-10-20
1000 Erschienen in
1000 Quellenangabe
  • 28(24):4148-4160
1000 FRL-Sammlung
1000 Copyrightjahr
  • 2019
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1093/hmg/ddz252 |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • Whilst heterozygous germline mutations in the ABRAXAS1 gene have been associated with a hereditary predisposition to breast cancer, their effect on promoting tumourigenesis at the cellular level has not been explored. Here, we demonstrate in patient-derived cells that the Finnish ABRAXAS1 founder mutation (c.1082G > A, Arg361Gln), even in the heterozygous state leads to decreased BRCA1 protein levels as well as reduced nuclear localization and foci formation of BRCA1 and CtIP. This causes disturbances in basal BRCA1-A complex localization, which is reflected by a restraint in error-prone DNA double-strand break repair pathway usage, attenuated DNA damage response and deregulated G2-M checkpoint control. The current study clearly demonstrates how the Finnish ABRAXAS1 founder mutation acts in a dominant-negative manner on BRCA1 to promote genome destabilization in heterozygous carrier cells.
1000 Sacherschließung
lokal Genetic Predisposition to Disease
lokal Breast Neoplasms/genetics
lokal Heterozygote [MeSH]
lokal Tumor Suppressor Proteins/genetics [MeSH]
lokal BRCA1 Protein/genetics [MeSH]
lokal Cell Cycle Checkpoints/genetics
lokal DNA Breaks, Double-Stranded [MeSH]
lokal DNA-Binding Proteins/genetics [MeSH]
lokal DNA Breaks, Double-Stranded
lokal Female
lokal Carrier Proteins/genetics [MeSH]
lokal BRCA1 Protein/genetics
lokal Heterozygote
lokal Carrier Proteins/genetics
lokal Genetic Predisposition to Disease [MeSH]
lokal DNA-Binding Proteins/genetics
lokal Female [MeSH]
lokal Humans
lokal DNA Repair [MeSH]
lokal Adult [MeSH]
lokal Germ-Line Mutation
lokal Humans [MeSH]
lokal Breast Neoplasms/genetics [MeSH]
lokal Genes, BRCA1 [MeSH]
lokal Adult
lokal Cell Cycle Checkpoints/genetics [MeSH]
lokal Germ-Line Mutation [MeSH]
lokal BRCA1 Protein/metabolism [MeSH]
lokal DNA Repair
lokal Genes, BRCA1
lokal BRCA1 Protein/metabolism
lokal Tumor Suppressor Proteins/genetics
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
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