24 DNA Replication and Cancer

Abstract

Cancer is a collection of diseases with different etiologies associated with a variety of molecular defects. Nevertheless, the cancer phenotype is invariably associated with loss of growth control leading to inappropriate or excessive proliferation of cells, and eventually, malignancy. The requirement for faithful duplication of genetic information in proliferating cells places DNA replication at the heart of the problem of cancer. For example, many of the molecular defects that lead to aberrant cell proliferation occur in pathways that converge on regulatory events controlling entry into S phase. This includes G₁ checkpoint pathways that block entry into S phase in response to DNA damage and other stresses (Chapter 18), as well as pRb and E2F-dependent pathways that up-regulate proteins required for licensing origins of DNA replication during reentry of cells into the cell cycle and at early stages of tumor progression (Chapters 3 and 16). In fact, the induction of licensing proteins in proliferating cells underlies their efficacy as diagnostic and prognostic markers for cancer (Chapter 25). Once cells enter S phase, the unique susceptibility to DNA damage of unwound DNA at replication forks can lead to genome instability, which is another salient feature of most, if not all, types of cancer. Genome instability can arise at DNA replication forks through mechanisms discussed in detail in other chapters of this book. These include loss of fidelity of the replication machinery (Chapter 20), replication errors that occur at sites of DNA damage lesions (Chapters 19 and 21), replication of unrepaired damage lesions...