Activity of DNA polymerase alpha in aging human fibroblasts

During the past decade intense investigation has: focused on cellular aging with the expectation of discovering factors that regulate the replication complex and contribute to the onset and progression of cellular aging. The most striking feature Of cellular aging is the failure of senescing diploid cells to enter or complete S phase of the cell cycle. The Gl/S phase trans ition is an initial critical step in the regulation of proliferation in euk aryotic cells, and significant advances have been made toward understanding the basic mechanisms of aging by identifying components of the macromolecu lar assemblies participating in the Gl/S transition. These studies have ide ntified multiple DNA polymerases and their. accessory factors, and have pro vided important strategies for investigating the molecular events that cont ribute to aging processes. DNA replication, repair and recombination in euk aryotic cells require the action of a variety of DNA polymerases, at least six of which are known, alpha, beta, gamma, delta, epsilon, and zeta. Among them the highly conserved DNA polymerase alpha -primase (pol alpha -primas e) is the only enzyme capable of initiating DNA replication at chromosomal origin sites and at sites of initiation of discontinuous synthesis of Okaza ki fragments on the lagging side of the replication fork. Numerous protein factors that play strategic roles in DNA replication have been identified a nd the understanding of their regulation has been an important step for ide ntifying the elements that are involved in, and possibly necessary fur, gov erning cellular senescence and aging. Tn this review we summarize the curre nt information regarding DNA pol alpha modulation during aging. We focus in particular on the coordinated actions of DNA pol alpha in the presence of other cellular proteins involved in the replication complex in the hope tha t understanding pol alpha interactions with components of the replication c omplex may provide insight into the mechanisms by which aging and age-relat ed diseases occur.