A study on the molecular mechanisms of BRCA1-mediated cell cycle regulation from a comprehensive protein interaction analysis approach

• Project/Area Number: 20590318
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: St.Marianna University School of Medicine
• Principal Investigator: WU Wenwen St.Marianna University School of Medicine, 医学部, 助教 (10434408)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2008: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: BRCA1 / HERC2 / 細胞周期 / 乳癌 / ユビキチン化 / DNA障害 / 複製フォーク / Claspin / G2 / Mチェックポイント / Chk1 / DNA修復 / BRCAI

Research Abstract

BRCA1 complex was comprehensively analyzed through the cell cycle. HERC2 specifically interacts with BRCA1. The interaction is maximal during the S phase of the cell cycle, and rapidly diminishes as cells enter mitosis. HERC2 is an E3 ligase to target the BARD1-uncoupled BRCA1 for degradation, to regulate BRCA1 stability. Concomitantly, HERC2 contributes to pre-replicative complex (pre-RC) formation and activation by the inducible phosphorylation of MCM protein and results in regulation of origin firing and replication. HERC2 plays a role in replication fork progression and stabilization with Claspin, to be involved in the G2/M checkpoint. The study elucidated HERC2 plays critical roles in BRCA1-mediated G2/M checkpoint.

Research Products

• [Journal Article] phosphorylated NPM1 to sites of DNA damage through RNF8-dependent ubiquitin conjugates. (2010)
  • Author(s): Koike A, Nishikawa H, Wu W, Okada Y, Venkitaraman AR, Ohta T
  • Journal Title: Cancer Res. 70 Pages: 6746-56
  • Peer Reviewed
• [Journal Article] is an E3 ligase that targets BRCA1 for degradation. (2010)
  • Author(s): Wu W, Sato K, Koike A, Nishikawa H, Koizumi H, Venkitaraman AR, Ohta T
  • Journal Title: Cancer Res. 70 Pages: 6384-92
  • Peer Reviewed
• [Journal Article] Prediction of breast cancer sensitivity to neoadjuvant chemotherapy based on status of DNA damage repair proteins. (2010)
  • Author(s): Asakawa H, Koizumi H, Koike A, Takahashi M, Wu W, Hirotaka Iwase, Fukuda M, Ohta T
  • Journal Title: Breast Cancer Research. 12:R17
  • Peer Reviewed
• [Journal Article] HERC2 is an E3 ligase that targets BRCA1 for degradation (2010)
  • Author(s): Wu w
  • Journal Title: Cancer Research Volume: 70 Pages: 6384-6392
  • Peer Reviewed
• [Journal Article] Recruitment of phosphorylated NPM1 to sites of DNA damage through RNF8-dependent ubiquitin conjugates (2010)
  • Author(s): Ikoike A
  • Journal Title: Cancer Research Volume: 70 Pages: 6746-6756
  • Peer Reviewed
• [Journal Article] rediction of breast cancer sensitivity to neoadjuvant chemotherapy based on status of DNA damage repair proteins (2010)
  • Author(s): Asakawa H
  • Journal Title: Breast Cancer Research Volume: 12(open access)
  • Peer Reviewed
• [Journal Article] Prediction of breast cancer sensitivity to neoadjuvant chemotherapy based on status of DNA damage repair proteins (2010)
  • Author(s): Asakawa H, et.al
  • Journal Title: Breast Cancer Research 12
  • Peer Reviewed
• [Journal Article] chemosensitivity of basal-like breast cancer based on BRCA1 dysfunction. (2009)
  • Author(s): Ohta T, Wu W, Koike A, Koizumi H, Fukuda M
  • Journal Title: Breast Cancer Research. 16 Pages: 268-74
  • Peer Reviewed
• [Journal Article] pathways by proteasome inhibitors corresponds to enhanced chemosensitivity of cells to DNA damage-inducing agents. (2009)
  • Author(s): Takeshita T, Wu Wu W, Koike A, Fukuda M. Ohta T
  • Journal Title: Cancer Chemother Pharmacol. 64 Pages: 1039-46
  • Peer Reviewed
• [Journal Article] BRCA1-associated protein 1 interferes with BRCA1/BARD1 RING heterodimer activity. (2009)
  • Author(s): Nishikawa H, Wu W, Koike A, Kojima R, Gomi H, Fukuda M, Ohta T
  • Journal Title: Cancer Res. 69 Pages: 111-119
  • Peer Reviewed
• [Journal Article] Perturbation of DNA repair pathways by proteasome inhibitors corresponds to enhanced chemosensitivity of cells to DNA damage-inducing agents (2009)
  • Author(s): Takeshita T
  • Journal Title: Cancer Chemother Pharmacol Epub ahead of print Pages: 1-8
  • Peer Reviewed
• [Journal Article] The ubiquitin E3 ligase activity of BRCA1 and its biological functions. (2008)
  • Author(s): Wu W, Koike A, Takeshita T, hta T
  • Journal Title: Cell Div. 3:1
  • Peer Reviewed
• [Journal Article] Modification of the Hepatic Mito-chondrial Proteome in Response to Ischemic Preconditioning following Ischemia-Reperfusion Injury of the Rat Liver. (2008)
  • Author(s): Oshima R, Nakano H, Katayama M, Sakurai J, Wu W, Koizumi S, Asano T, Watanabe T, Asakura T, Ohta T, Otsubo T
  • Journal Title: Eur Surg Res. 40 Pages: 247-255
  • Peer Reviewed
• [Presentation] The E3 ligase activity of HERC2 regulates BRCA1-mediated G2/M checkpoint function independent of BARD1 (2009)
  • Author(s): 呉文文
  • Organizer: 5th Cold Spring Harbor Meeting On The ubiquitin Family
  • Place of Presentation: Cold Spring Harbor, NY
  • Year and Date: 2009-05-22
• [Presentation] THE E3 LIGASE ACTIVITY OF HERC2 REGULATES BRCA1-MEDIATED G2/MCHECKPOINT FUNCTION INDEPENDENT OF BARD1 (2009)
  • Author(s): Wenwen Wu
  • Organizer: 5th Cold Spring Harbor Meeting On The ubiquitin Family
  • Place of Presentation: Cold Spring Harbor, NY
  • Year and Date: 2009-04-22
• [Presentation] BRCA1を分解するユビキチンリガーゼの同定 (2008)
  • Author(s): 呉文文
  • Organizer: 第16回乳癌学会学術総会
  • Place of Presentation: 大阪
  • Year and Date: 2008-09-27