chapter  9
26 Pages

Involvement of Poly(ADP-Ribose) Polymerase in the Cellular Response to DNA Damage

To ensure accurate transmission of genetic information in dividing cells, specific biochemical pathways maintain integrity. Fundamental to these pathways is the recognition of genomic lesions by specific proteins, which signals the presence of DNA damage to nuclear factors involved in DNA repair and cell survival. DNA strand breaks, generated either directly by genotoxic agents (oxygen radicals, ionizing radiation, monofunctional alkylating agents) or indirectly following enzymatic incision of a DNA-base lesion, trigger the synthesis of poly(ADP-ribose) by the enzyme poly(ADP-ribose) polymerase (PARP). PARP (E.C. 2.4.2.30) is a nuclear zinc-finger DNA-binding protein that detects DNA strand breaks. At a site of breakage, PARP catalyzes the transfer of the ADP-ribose moiety from the respiratory coenzyme NAD

to a limited number of protein acceptors (Figure 9.1) involved in chromatin architecture (histones H1, H2B, HMG proteins, lamin B) or in DNA metabolism (DNA replication factors, topoisomerases including PARP itself).