Sperm-specific mechanism that induces the gross chromosomal rearrangements

2011 Fiscal Year Final Research Report

• Project/Area Number: 21390101
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Human genetics
• Research Institution: Fujita Health University
• Principal Investigator: KURAHASHI Hiroki 藤田保健衛生大学, 総合医科学研究所, 教授 (30243215)
• Project Period (FY): 2009 – 2011
• Keywords: 染色体転座 / 切断点 / 回文配列 / パリンドローム / 十字架型DNA / 非B型DNA / 染色体再構成 / 染色体構造異常

Research Abstract

Gross chromosomal rearrangements(GCRs) are often generated by illegitimate repair between two DNA breakages at regions with nucleotide sequences that potentially adopt a non-B DNA structure. We previously established a plasmid-based model system that recapitulates palindrome-mediated recurrent translocations in humans, and demonstrated that cruciform DNA is required for the rearrangements. In this study, we show that two sequential reactions that cleave the cruciform structures induce the translocation : GEN1-mediated resolution that cleaves diagonally at the four-way junction of the cruciform, and Artemis-mediated opening of the subsequently formed hairpin ends. These two intrinsic pathways that normally fulfill vital functions independently, Holliday junction resolution in homologous recombination and coding joint formation in rearrangement of antigen-receptor genes, act upon the unusual DNA conformation in concert and lead to these recurrent GCRs in humans.

Research Products

• [Journal Article] DNA secondary structure is influenced by genetic variation and alters susceptibility to de novo translocation (2011)
  • Author(s): Kato T, Inagaki H, Tong M, Kogo H, Ohye T, Yamada K, Tsutsumi M, Emanuel BS, Kurahashi H
  • Journal Title: Mol Cytoenet Volume: 4 Pages: 18
  • Peer Reviewed
• [Journal Article] Paternal origin of the de novo constitutional t(11 ; 22)(q23 ; q11) (2010)
  • Author(s): Ohye T, Inagaki H, Kogo H, Tsutsumi M, Kato T, Tong M, Macville M, Medne L, Zackai EH, Emanuel BS, Kurahashi H
  • Journal Title: Eur J Hum Genet Volume: 18(7) Pages: 783-7
  • Peer Reviewed
• [Journal Article] Polymorphisms of the 22q11.2 breakpoint region influence the frequency of de novo constitutional t(11 ; 22) s in sperm (2010)
  • Author(s): Tong M, Kato T, Yamada K, Inagaki H, Kogo H, Ohye T, Tsutsumi M, Wang J, Emanuel BS, Kurahashi H
  • Journal Title: Hum Mol Genet Volume: 19(13) Pages: 2630-7
  • Peer Reviewed
• [Journal Article] A new palindrome-mediated recurrent translocation with 3 : 1 meiotic non-disjunction : the t(8 ; 22)(q24.13 ; q11.21) (2010)
  • Author(s): Sheridan MB, Kato T, Haldeman-Englert C, Jalali GR, Milunsky JM, Zou Y, Klaes R, Gimelli S, Gemmill RM, Drabkin HA, Hacker AM, Brown J, Tomkins D, Shaikh TH, Kurahashi H, Zackai EH, Emanuel BS
  • Journal Title: Am J Hum Genet Volume: 87(2) Pages: 209-18
  • Peer Reviewed
• [Journal Article] The constitutional t(11 ; 22): implications for a novel mechanism responsible for gross chromosomal rearrangement (2010)
  • Author(s): Kurahashi H, Inagaki H, Kogo H, Ohye T, Tsutsumi M, Kato T, Tong M, Emanuel BS
  • Journal Title: Clin Genet Volume: 78(4) Pages: 299-309
  • Peer Reviewed
• [Journal Article] Chromosomal instability mediated by non-B DNA : Cruciform conformation and not DNA sequence is responsible for recurrent translocation in humans (2009)
  • Author(s): Inagaki H, Ohye T, Kogo H, Kato T, Bolor H, Taniguchi M, Shaikh TH, Emanuel BS, Kurahashi H
  • Journal Title: Genome Res Volume: 19(2) Pages: 191-198
  • Peer Reviewed
• [Journal Article] Impaired DNA replication prompts deletions within palindromic sequences, but does not induce translocations in human cells (2009)
  • Author(s): Kurahashi H, Inagaki H, Kato T, Hosoba E, Kogo H, Ohye T, Tsutsumi M, Bolor H, Tong M, Emanuel BS
  • Journal Title: Hum Mol Genet Volume: 18(18) Pages: 3397-3406
  • Peer Reviewed
• [Journal Article] Recent advance in our understanding of the molecular nature of chromosomal abnormalities (2009)
  • Author(s): Kurahashi H, Bolor H, Kato T, Kogo H, Tsutsumi M, Inagaki H, Ohye T
  • Journal Title: J Hum Genet Volume: 54(5) Pages: 253-260
  • Peer Reviewed
• [Presentation] Mechanism of recurrent translocation t(11 ; 22) initiated by cruciform conformation of palindromic sequences (2011)
  • Author(s): Inagaki H, Ohye T, Kogo H, Tsutsumi M, Kato T, Tong M, Emanuel BS, Kurahashi H
  • Organizer: The 12th International Congress of Human Genetics
  • Place of Presentation: Montreal, Canada
  • Year and Date: 20111011-15
• [Presentation] Identification of a novel palindrome mediated translocation associated with the t(3 ; 8) of hereditary renal cancer (2011)
  • Author(s): Kato T, Sheridan MB, Hacker AM, Inagaki H, Glover TW, Plon SE, Drabkin HA, Gemmill RM, Kurahashi H, Emanuel BS
  • Organizer: The 12th International Congress of Human Genetics
  • Place of Presentation: Montreal, Canada
  • Year and Date: 20111011-15
• [Presentation] GEN1 resolves cruciform-forming palindromic DNA leading to a recurrent translocation in humans (2011)
  • Author(s): Inagaki H, Ohye T, Kogo H, Tsutsumi M, Kato T, Tong M, Emanuel BS, Kurahashi H
  • Organizer: Kyestone Symposia : Functional consequences of structural variation in the genome
  • Place of Presentation: Steamboat Springs, USA
  • Year and Date: 20110108-13
• [Presentation] GEN1 resolves cruciform-forming palindromic DNA leading to a recurrent translocation in humans (2010)
  • Author(s): Inagaki H, Ohye T, Kogo H, Tsutsumi M, Kato T, Tong M, Emanuel BS, Kurahashi H
  • Organizer: The American Society of Human Genetics 60th Annual Meeting
  • Place of Presentation: Washington DC, USA
  • Year and Date: 20101102-06
• [Presentation] GEN1 resolves cruciform-forming palindromic DNA leading to a recurrent translocation in humans (2010)
  • Author(s): Inagaki H, Ohye T, Kogo H, Tsutsumi M, Kato T, Tong M, Emanuel BS, Kurahashi H
  • Organizer: The 7th 3R Symposium
  • Place of Presentation: Toyama, Japan
  • Year and Date: 20101026-30
• [Presentation] Palindrome-mediated chromosomal translocation in humans. (2010)
  • Author(s): Kurahashi H
  • Organizer: FASEB Summer Research Conferences. Biological Impact of Alternatively Structured DNA
  • Place of Presentation: Colorado, USA
  • Year and Date: 20100705-10
• [Presentation] Paternal origin of the de novo constitutional t(11 ; 22)(q23 ; q11) (2010)
  • Author(s): Ohye T, Inagaki H, Kogo H, Tsutsumi M, Kato T, Tong M, Macville MVE, Medne L, Zackai EH, Emanuel BS, Kurahashi H
  • Organizer: European Society of Human Genetics Conference 2010
  • Place of Presentation: Gothenburg, Sweden
  • Year and Date: 20100612-15
• [Presentation] Parental origin of de novo t(11 ; 22)(q23 ; q11) (2009)
  • Author(s): Ohye T, Inagaki H, Kogo H, Tsutsumi M, Kato T, Tong M, Macville MV, Medne L, Zackai EH, Emanuel BS, Kurahashi H
  • Organizer: 59th annual meeting of American Society of Human Genetics
  • Place of Presentation: Hawai, USA
  • Year and Date: 20091020-24
• [Presentation] Two successive cleavages in palindrome-mediated translocation (2009)
  • Author(s): Kurahashi H, Inagaki H, Kato T, Ohye T, Kogo H, Shaikh TH, Emanuel BS
  • Organizer: Genome Instability and DNA Repair
  • Place of Presentation: Taos, USA
  • Year and Date: 20090301-06
• [Book] Cruciform DNA. Encyclopedia of Genetics, 2nd Edition
  • Author(s): Inagaki H, Kurahashi H
  • Publisher: Elsevier(in press)