Regulatory mechanisms of CtIP nuclease during DNA crosslink repair

2014 Fiscal Year Final Research Report

• Project/Area Number: 24310042
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Risk sciences of radiation/Chemicals
• Research Institution: Kyoto University
• Principal Investigator: TAKATA Minoru 京都大学, 放射線生物研究センター, 教授 (30281728)
• Co-Investigator(Kenkyū-buntansha): UNNO Junya 京都大学, 放射線生物研究センター, 研究員 (50614153) ; KATSUKI Yoko 京都大学, 放射線生物研究センター, 研究員 (00645377)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: Fanconi貧血 / FANCD2 / CtIP / ユビキチン化 / DNAクロスリンク損傷 / DNA損傷修復

Outline of Final Research Achievements

The Fanconi anemia (FA) pathway is critically involved in the maintenance of hematopoietic stem cells and the suppression of carcinogenesis. A key FA protein, FANCD2, is monoubiquitinated and accumulates in chromatin in response to DNA interstrand crosslinks (ICLs), where it coordinates DNA repair through mechanisms that are still poorly understood. Here we report that CtIP protein is a direct interactor of FANCD2. A region spanning amino acids 166 to 273 of CtIP, and monoubiquitination of FANCD2, were both essential for the FANCD2-CtIP interaction and MMC-induced CtIP foci. Remarkably, both FANCD2 and CtIP were critical for MMC-induced RPA2 hyperphosphorylation, an event that accompanies end resection of double strand breaks. Collectively, our results reveal a role of monoubiquitinated FANCD2 in end resection, anchoring CtIP to chromatin during ICL repair.

Free Research Field

分子放射線生物学