Functional Analysis of BARD1 Missense Variants in Homology-Directed Repair of DNA Double Strand Breaks

Human Mutation
Cindy LeeJeffrey D Parvin

Abstract

Genes associated with hereditary breast and ovarian cancer (HBOC) are often sequenced in search of mutations that are predictive of susceptibility to these cancer types, but the sequence results are frequently ambiguous because of the detection of missense substitutions for which the clinical impact is unknown. The BARD1 protein is the heterodimeric partner of BRCA1 and is included on clinical gene panels for testing for susceptibility to HBOC. Like BRCA1, it is required for homology-directed DNA repair (HDR). We measured the HDR function of 29 BARD1 missense variants, 27 culled from clinical test results and two synthetic variants. Twenty-three of the assayed variants were functional for HDR; of these, four are known neutral variants. Three variants showed intermediate function, and three others were defective in HDR. When mapped to BARD1 domains, residues crucial for HDR were located in the N- and C- termini of BARD1. In the BARD1 RING domain, critical residues mapped to the zinc-coordinating amino acids and to the BRCA1-BARD1 binding interface, highlighting the importance of interaction between BRCA1 and BARD1 for HDR activity. Based on these results, we propose that the HDR assay is a useful complement to genetic analyses t...Continue Reading

References

Nov 5, 1999·Molecular Cell·M E MoynahanM Jasin
May 19, 2001·Genes & Development·T LudwigA Efstratiadis
Sep 27, 2001·Nature Structural Biology·P S BrzovicR E Klevit
Oct 11, 2001·Proceedings of the National Academy of Sciences of the United States of America·V JoukovD M Livingston
Jan 5, 2002·The Journal of Biological Chemistry·Joanna R MorrisEllen Solomon
Jan 16, 2002·Current Opinion in Genetics & Development·Richard Baer, Thomas Ludwig
Mar 5, 2002·Genome Research·Pauline C Ng, Steven Henikoff
Nov 15, 2002·The Journal of Biological Chemistry·Yan XiaTony Hunter
Jun 6, 2003·Current Opinion in Cell Biology·Lea M Starita, Jeffrey D Parvin
Oct 16, 2003·Molecular and Cellular Biology·Ulrica K WestermarkMary Ellen Moynahan
May 29, 2004·The Journal of Biological Chemistry·Atish D ChoudhuryRichard Baer
Dec 8, 2005·European Journal of Human Genetics : EJHG·Pia VahteristoHeli Nevanlinna
Feb 21, 2006·Cancer Research·Amanda M SimonsJeffrey D Parvin
Jan 11, 2007·British Journal of Cancer·E Levy-Lahad, E Friedman
Apr 10, 2007·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Sining Chen, Giovanni Parmigiani
Sep 13, 2007·The Journal of Biological Chemistry·Marsha LauferRichard Baer
Nov 29, 2007·Journal of the National Cancer Institute·Yu Chuan TaiSining Chen
Dec 27, 2007·JAMA : the Journal of the American Medical Association·Esther M JohnAlice S Whittemore
Dec 29, 2007·Nature Genetics·Michael R Stratton, Nazneen Rahman
Feb 7, 2008·Nucleic Acids Research·Nurit MirkinFrida E Kleiman
Apr 30, 2008·Proceedings of the National Academy of Sciences of the United States of America·Reena ShakyaThomas Ludwig
Jun 12, 2008·Annual Review of Genomics and Human Genetics·Clare Turnbull, Nazneen Rahman
Apr 3, 2009·Nucleic Acids Research·François-Olivier DesmetChristophe Béroud
Apr 1, 2010·Nature Methods·Ivan A AdzhubeiShamil R Sunyaev
Jul 16, 2010·Cancer Research·Wenwen WuTomohiko Ohta
Feb 24, 2011·Breast Cancer Research and Treatment·Magdalena RatajskaJanusz Limon
Jul 1, 2011·Cancer Treatment Reviews·A CerbinskaiteR J Edmondson
Aug 3, 2011·Journal of Cancer Research and Clinical Oncology·Da-Peng DingWen-Ling Zheng
Oct 19, 2011·Proceedings of the National Academy of Sciences of the United States of America·Tom WalshElizabeth M Swisher
Jan 24, 2012·Gynecologic Oncology·Kathryn P Pennington, Elizabeth M Swisher
May 1, 2012·Molecular Biology Reports·Patricio Gonzalez-HormazabalLilian Jara
Aug 28, 2012·International Journal of Oncology·Srdjan NovakovićAleš Vakselj
Oct 12, 2012·PloS One·Yongwook ChoiAgnes P Chan

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Citations

Aug 16, 2016·Nature Reviews. Cancer·Finn Cilius NielsenClaus Storgaard Sørensen
Jan 26, 2018·Proceedings of the National Academy of Sciences of the United States of America·Mikaela D StewartRachel E Klevit
Mar 30, 2019·PLoS Genetics·Aleksandra I AdamovichJeffrey D Parvin
Jan 29, 2020·3 Biotech·Pasupuleti Santhosh KumarPotukuchi Venkata Gurunadha Krishna Sarma
Mar 14, 2020·Health Physics·Hanns Leonhard KaatschBenjamin Valentin Becker
Jun 22, 2017·Scientific Reports·Rajan Kumar ChoudharyAshok K Varma
May 10, 2017·International Journal of Cancer. Journal International Du Cancer·Suhair Lolas HamamehMoein Kanaan
Aug 3, 2019·Cold Spring Harbor Molecular Case Studies·Ming Ren TohJoanne Ngeow
Jun 3, 2018·Molecular Cancer Research : MCR·Yuki YoshinoNatsuko Chiba
Apr 1, 2021·Cell Reports·Elizabeth V MintenDavid S Yu

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