Amplification of TLK2 Induces Genomic Instability via Impairing the G2/M Checkpoint

摘要

Managing aggressive breast cancers with enhanced chromosomal instability 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 (ER) positive breast cancers. In this study, it was discovered that TLK2 amplification and overexpression mechanistically impairs Chk1/2-induced DNA-damage checkpoint signaling, leading to a G2/M checkpoint defect, delayed DNA repair process, and increased chromosomal instability. 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 chromosomal instability, 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-positive breast cancers.IMPLICATIONS: Targeting TLK2 presents an attractive therapeutic strategy for the TLK2-amplified breast cancers that possess enhanced genomic instability and aggressiveness.