DNA Fragmentation as a Developmental Program for Cellular Aging in Cardiac Muscle

Abstract

Several years ago we determined that semiconservative DNA replication in the intact rat heart and in isolated individual cardiac muscle cells essentially ceases by the third week of postnatal development (1–3). Temporally correlated with this loss of DNA replicative ability was the disappearance from these cells of the putative replicative DNA polymerase, DNA polymerase a (1,3). An obvious question to ask of this data was: does DNA synthesis cease in these cells because the activity of this enzyme is lost, or is the activity of this enzyme lost because DNA synthesis ceases? Which is cause and which is effect? In an attempt to answer this question, DNA template availability (capacity to prime for DNA replication) and the number of 3’-OH termini in the DNA (origins of DNA replication) were measured in cardiac muscle nuclei and chromatin prepared at various times during the developmental period when DNA replication is being and has been restricted. These parameters were assessed using several different exogenous DNA polymerases (4). It was observed that DNA template and 3’-OH termini available to exogenously added DNA polymerases do not change as cardiac muscle differentiates and the rate of DNA synthesis ceases (4) (Fig. 1). It was concluded from these experiments that DNA replication ceases in these cells because the activity of a replicative DNA polymerase is lost, rather than the activity of this enzyme being lost because DNA synthesis ceases.