Molecular and biological roles of Ape1 protein in mammalian base excision repair.
Many oxidative DNA lesions are handled well by base excision repair (BER), but some types may be problematic. Recent work indicates that 2-deoxyribonolactone (dL) is such a lesion by forming stable, covalent cross-links between the abasic residue and DNA repair proteins with lyase activity. In the case of DNA polymerase beta, the reaction is potentiated by incision of dL by Ape1, the major mammalian AP endonuclease. When repair is prevented, polymerase beta is the most reactive cross-linking protein in whole-cell extracts. Cross-linking with dL is largely avoided by processing the damage through the "long-patch" (multinucleotide) BER pathway. However, if excess damage leads to the accumulation of unrepaired oxidative lesions in DNA, there may be a danger of polymerase beta-mediated cross-link formation. Understanding how cells respond to such complex damage is an important issue. In addition to its role in defending against DNA damage caused by exogenous agents, Ape1 protein is essential for coping with the endogenous DNA damage in human cells grown in culture. Suppression of Ape1 using RNA-interference technology causes arrest of cell proliferation and activation of apoptosis in various cell types, correlated with the accumulation of unrepaired abasic DNA damage. Notably, all these effects are reversed by expression of the unrelated protein Apn1 of S. cerevisiae, which shares only the enzymatic repair function with Ape1 (AP endonuclease).
Demple
Bruce
B
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA. bdemple@hsph.harvard.edu
Sung
Jung-Suk
JS
D000818:Animals; D017209:Apoptosis; D001080:Apurinic Acid / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D013400:Sugar Acids / Q000737:chemistry / Q000378:metabolism
D013400:Sugar Acids; D001080:Apurinic Acid; C056405:2,4,5-trihydroxypentanoic acid gamma-lactone; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase