Functional Analysis of Chk2-Kiaa0170 Interaction
Abstract
Chk2 is a critical regulator of DNA damage repair checkpoint controls. Mutations in Chk2 confer an increased risk of breast cancer. However, the regulation of Chk2-mediated pathways is still not clear. We previously identified Kiaa0170 (later renamed MDC1, Mediator of DNA Damage Checkpoint Protein 1), interacts with Chk2 after DNA damage. We hypothesized that MDC1 is a key regulator of Chk2-dependent pathways, and is directly involved in DNA repair and cell cycle control. Dysfunction of MDC1-Chk2 pathway could be a key event in tumorigenesis. During funding period, we mapped the interaction sites responsible for the Chk2-MDC1 interaction (Task 1). We also show that MDC1 regulates Chk2-dependent cell cycle checkpoint and radiation-induced apoptosis (Task 2). Finally we generated MDC1 knockout mice and provide evidence at the organismal level that MDC1 is a critical regulator of the DNA damage response pathway and genomic stability (revised Task 3). MDC1 mice also show increased tumor incidence, suggesting that MDC1, like Chk2, is a potential tumor suppressor. Our work provide novel insight into the mechanism of the DNA damage response pathway and tumor suppression.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2006
- Accession Number
- ADA462752
Entities
People
- Zhenkun Lou