A role of the mitotic spindle checkpoint in the cellular response to DNA replication stress

✍ Scribed by Anette Duensing; Xiaoyi Teng; Ying Liu; Michelle Tseng; Nicole Spardy; Stefan Duensing

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 328 KB
• Volume: 99
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/jcb.20962

✦ Synopsis

Abstract

Replication stress is a frequent and early event during tumorigenesis. Whereas the cellular responses to a persistent block of replication fork progression have been extensively studied, relatively little is known about how cells respond to low‐intensity replication stress. However, transient replication fork perturbations are likely to occur even more frequently in tumor cells than a permanent replication arrest. We report here that transient, low intensity replication stress leads to a rapid activation of the DNA replication checkpoint but to a significantly delayed apoptotic response in a small but significant number of cells. This late apoptotic response was independent of p53 and we found evidence for cell death during mitosis in a proportion of cells. To further explore the role of p53 in the response to replication stress, we analyzed mouse embryonic fibroblasts (MEFs) deficient of p53 in comparison to wild‐type or p63‐ or p73‐deficient MEFs. We detected a significant increase of apoptosis and morphological signs of failed mitosis such as multinucleation in p53‐deficient MEFs following replication stress, but not in wild‐type or p63‐ or p73‐deficient cells. Multinucleated p53‐deficient MEFs frequently retained cyclin B1 expression indicating a persistently activated mitotic spindle checkpoint. Collectively, our results suggest that the cellular response to replication stress involves the mitotic spindle checkpoint in a proportion of cells. These findings imply that the mitotic spindle checkpoint may act in concert with DNA damage and cell‐cycle checkpoints as an early anti‐tumor barrier and provide a possible explanation for its frequent relaxation in human cancer. J. Cell. Biochem. 99: 759–769, 2006. © 2006 Wiley‐Liss, Inc.