STRUCTURE AND FUNCTION OF MAMMALIAN DNA LIGASES

DNA joining events are required for the completion of DNA replication, DNA excision repair and genetic recombination. Five DNA ligase activi ties, I-V, have been purified from mammalian cell extracts and three m ammalian LIG genes, LIG1, LIG3 and LIG4, have been cloned. During DNA replication, the joining of Okazaki fragments by the LIG1 gene product appears to be mediated by an interaction with proliferating cell nucl ear antigen (PCNA). This interaction may also occur during the complet ion of mismatch, nucleotide excision and base excision repair (BER). I n addition, DNA ligase I participates in a second BER pathway that is carried out by a multiprotein complex in which DNA ligase I interacts directly with DNA polymerase beta. DNA ligase III alpha and DNA ligase III beta, which are generated by alternative splicing of the LIG3 gen e, can be distinguished by their ability to bind to the DNA repair pro tein, XRCC1. The interaction between DNA ligase III alpha and XRCC1, w hich occurs through BRCT motifs in the C-termini of these polypeptides , implicates this isoform of DNA ligase III in the repair of DNA singl e-strand breaks and BER. DNA ligase II appears to be a proteolytic fra gment of DNA ligase III alpha. The restricted expression of DNA ligase III beta suggests that this enzyme may function in the completion of meiotic recombination ol in a postmeiosis DNA repair pathway. Complex formation between DNA ligase IV and the DNA repair protein XRCC4 invol ves the C-terminal region of DNA ligase IV, which contains two BRCT mo tifs. This interaction, which stimulates DNA joining activity, implies that DNA ligase IV functions in V(D)J recombination and non-homologou s end-joining of DNA double-strand breaks. At the present time, it is not known whether DNA ligase V is derived from one of the known mammal ian LIG genes or is the product of a novel gene. (C) 1998 Elsevier Sci ence B.V.