Reducing MCM levels in human primary T cells during the G(0)-> G(1) transition causes genomic instability during the first cell cycle

S. J. Orr, T. Gaymes, D. Ladon, C. Chronis, B. Czepulkowski, R. Wang, G. J. Mufti, E. M. Marcotte, N. S. B. Thomas

    Research output: Contribution to journalArticlepeer-review

    34 Citations (Scopus)

    Abstract

    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
    Original languageEnglish
    Pages (from-to)3803 - 3814
    Number of pages12
    JournalOncogene
    Volume29
    Issue number26
    DOIs
    Publication statusPublished - 1 Jul 2010

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