Replicative enzymes and ageing: importance of DNA polymerase alpha function to the events of cellular ageing.

A hallmark of cellular ageing is the failure of senescing cells to initiate DNA synthesis and transition from G1 into S phase of the cell cycle. This transition is normally dependent on or concomitant with expression of a set of genes specifying cellular proteins, some of which directly participate in DNA replication. Deregulation of this gene expression may play a pivotal role in the ageing process. The number of known enzymes and co-factors required to maintain integrity of the genome during eukaryotic DNA replication has increased significantly in the past few years, and includes proteins essential for DNA replication and repair, as well as for cell cycle regulation. In eukaryotic cells, ranging from yeast to man, a replicative enzyme essential for initiation of transcription is DNA polymerase alpha (pol alpha), the activity of which is coordinately regulated with the initiation of DNA synthesis. DNA pol alpha, by means of its primase subunit, has the unique ability to initiate de novo DNA synthesis, and as a consequence, is required for the initiation of continuous (leading-strand) DNA synthesis at an origin of replication, as well as for initiation of discontinuous (lagging-strand) DNA synthesis. The dual role of the pol alpha-primase complex makes it a potential interactant with the regulatory mechanisms controlling entry into S phase. The purpose of this review is to address the regulation and/or modulation of DNA pol alpha during ageing that may play a key role in the cascade of events which ultimately leads to the failure of old cells to enter or complete S phase of the cell cycle.