Biomedical subjects

Ronald Laskey

Publications and source records attributed to Ronald Laskey.

3 recordsLinked to original sources

PubMed2005

The Croonian Lecture 2001 hunting the antisocial cancer cell: MCM proteins and their exploitation.

Replicating large eukaryotic genomes presents the challenge of distinguishing replicated regions of DNA from unreplicated DNA. A heterohexamer of minichromosome maintenance (MCM) proteins is essential for the initiation of DNA replication. MCM proteins are loaded on to unreplicated DNA before replication begins and displaced progressively during replication. Thus, bound MCM proteins license DNA for one, and only one, round of replication and this licence is reissued each time a cell divides. MCM proteins are also the best candidates for the replicative helicases that unwind DNA during replication, but interesting questions arise about how they can perform this role, particularly as they are present on only unreplicated DNA, rather than clustered at replication forks. Although MCM proteins are bound and released cyclically from DNA during the cell cycle, higher eukaryotic cells retain them in the nucleus throughout the cell cycle. In contrast, MCMs are broken down when cells exit the cycle by quiescence or differentiation. We have exploited these observations to develop screening tests for the common carcinomas, starting with an attempt to improve the sensitivity of the smear test for cervical cancer. MCM proteins emerge as exceptionally promising markers for cancer screening and early diagnosis.

Biomarkers, Tumor↗

PubMed2003

Translational approaches to improving cervical screening.

Screening programmes for cervical cancer using the current test--the Pap smear--have markedly reduced the incidence of the disease. However, an individual Pap test is of limited sensitivity and is difficult and expensive to perform. Increased understanding of the molecular pathogenesis of cervical cancer indicates that new approaches to screening might offer increased accuracy, affordability and the potential for automation. Such approaches exemplify how improved understanding of the biology of neoplasia might be translated into clinical benefit.

Acetic Acid↗

PubMed2002

The MCM3 acetylase MCM3AP inhibits initiation, but not elongation, of DNA replication via interaction with MCM3.

Minichromosome maintenance (MCM) proteins are essential components of pre-replication complexes, which limit DNA replication to once per cell cycle. MCM3 acetylating protein, MCM3AP, binds and acetylates MCM3 and inhibits cell cycle progression. In the present study, we examined inhibition of the cell cycle by MCM3AP in a cell-free system. We show here that wild type MCM3AP, but not the acetylase-deficient mutant, inhibits initiation of DNA replication, but not elongation. Both wild type and acetylase-deficient mutant MCM3AP, however, can bind to chromatin through interaction with MCM3. These results indicate that MCM3 acetylase activity of MCM3AP is required to inhibit initiation of DNA replication and that association of MCM3AP to chromatin alone is not sufficient for the inhibition. We also show that interaction between MCM3 and MCM3AP is essential for nuclear localization and chromatin binding of MCM3AP. Furthermore, the chromatin binding of MCM3AP is temporally correlated with that of endogenous MCM3 when cells were released from mitosis. Hence, MCM3AP is a potent natural inhibitor of the initiation of DNA replication whose action is mediated by interaction with MCM3.

Acetyltransferases↗