Amplification of TLK2 Induces Genomic Instability via Impairing the G2–M Checkpoint
Abstract
Managing aggressive breast cancers with enhanced chromosomal instability (CIN) is a significant challenge in clinics. Previously, we described that a cell cycle–associated kinase called Tousled-like kinase 2 (TLK2) is frequently deregulated by genomic amplifications in aggressive estrogen receptor–positive (ER+) breast cancers. In this study, it was discovered that TLK2 amplification and overexpression mechanistically impair Chk1/2-induced DNA damage checkpoint signaling, leading to a G2–M checkpoint defect, delayed DNA repair process, and increased CIN. In addition, TLK2 overexpression modestly sensitizes breast cancer cells to DNA-damaging agents, such as irradiation or doxorubicin. To our knowledge, this is the first report linking TLK2 function to CIN, in contrast to the function of its paralog TLK1 as a guardian of genome stability. This finding yields new insight into the deregulated DNA damage pathway and increased genomic instability in aggressive ER+ breast cancers.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 01, 2016
- Source ID
- 10.1158/1541-7786.mcr-16-0161
Entities
People
- Jamunarani Veeraraghavan
- Jin-ah Kim
- Kaiyi Li
- Meenakshi Anurag
- Rachel Schiff
- Xiao-song Wang
Organizations
- Baylor College of Medicine
- Congressionally Directed Medical Research Programs
- National Institutes of Health
- Susan G. Komen for the Cure
- University of Pittsburgh