Journal
ONCOGENE
Volume 29, Issue 26, Pages 3803-3814Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2010.138
Keywords
cell cycle; MCM; chromosomal abnormalities; DNA damage; premature chromatid separation
Funding
- Leukaemia Research Fund
- Department of Trade and Industry (dti)
- British Society for Haematology
- Welch and Packard Foundations
- National Institutes of Health (NIH)
Ask authors/readers for more resources
DNA replication is tightly regulated, but paradoxically there is reported to be an excess of MCM DNA replication proteins over the number of replication origins. Here, we show that MCM levels in primary human T cells are induced during the G(0)-> G(1) transition and are not in excess in proliferating cells. The level of induction is critical as we show that a 50% reduction leads to increased centromere separation, premature chromatid separation (PCS) and gross chromosomal abnormalities typical of genomic instability syndromes. We investigated the mechanisms involved and show that a reduction in MCM levels causes dose-dependent DNA damage involving activation of ATR & ATM and Chk1 & Chk2. There is increased DNA mis-repair by non-homologous end joining (NHEJ) and both NHEJ and homologous recombination are necessary for Mcm7-depleted cells to progress to metaphase. Therefore, a simple reduction in MCM loading onto DNA, which occurs in cancers as a result of aberrant cell cycle control, is sufficient to cause PCS and gross genomic instability within one cell cycle. Oncogene (2010) 29, 3803-3814; doi: 10.1038/onc.2010.138; published online 3 May 2010
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available