Cell‐cycle‐dependent regulation of DNA replication and its relevance to cancer pathology

Abstract

The highly orchestrated process of DNA replication ensures the accurate inheritance of genetic information from one cell generation to the next. The exact execution of DNA replication depends on a large number of proteins that are being studied extensively in the cell cycle field. Some of these proteins, such as the minichromosome maintenance proteins (MCMs), are essential for the process of DNA replication itself. Others such as geminin are specifically required to limit DNA replication to once per cell cycle. Together, these proteins protect the stability of the human genome in cycling cells. Their expression has been compared with routinely used proliferation markers, such as Ki-67 (MIB-1) and proliferating cell nuclear antigen (PCNA), which fulfil the requirements of molecular tumour markers to varying extents. However, it is with regard to the depth of our understanding of antigen biology that the MCM proteins and geminin qualify exceptionally well as novel cellcycle biomarkers for routine use in clinical practice, particularly in cancer detection and estimation of prognosis. Expression microarray analysis has also independently identified MCMs and their interacting proteins as determinants of the inherent aggressiveness of a wide range of epithelial malignancies.

Minichromosome maintenance protein 6, a proliferation marker superior to Ki-67 and independent predictor of survival in patients with mantle cell lymphoma

“…This fact could also explain why the blastoid and classical subtype had no significant difference in the MCM6 expression as a marker for the G1 arrest and not as a proliferation marker. As this cell cycle arrest has been shown by others Eward et al, 2004;Obermann et al, 2005;Tachibana et al, 2005), we could demonstrate that this has a clinical relevance in patients with MCLs. Our data on expression of repp86 in MCL (Schrader et al, 2005) showed that real proliferation activity is an important prognostic factor in MCL.…”

DNA damage-induced S phase arrest in human breast cancer depends on Chk1, but G2arrest can occur independently of Chk1, Chk2 or MAPKAPK2

“…To further establish the role of Chk1 in G 2 arrest, it was necessary to resolve whether the ΔChk1 cells observed by flow cytometry as arrested in G 2 /M were in fact in G 2 or M. Geminin is a marker of cells in S and G 2 ; it is proteolyzed in mitosis and does not accumulate again until cells enter S. 36 While phosphorylation of histone H3 is frequently used as a marker of mitosis, this is only a transient signal that can not be used to detect post-mitotic tetraploid cells. This limitation is resolved by using geminin.…”

Expression of Mcm2, geminin and Ki67 in normal oral mucosa, oral epithelial dysplasias and their corresponding squamous-cell carcinomas

“…Geminin, a novel proliferation marker is present from the G 1 -S transition to early M phases (McGarry and Kirschner, 1998) and helps to regulate cell-cycle initiation by impeding a second prereplication complex assembly once replication has started (McGarry and Kirschner, 1998;Tachibana et al, 2005). It has also been suggested that geminin levels may be altered in cancer cells as it has been found to be overexpressed in several cancer cell lines (Xouri et al, 2004).…”