oa DNA Ligases I and III Cooperate to Mediate Alternative Non-homologous End-joining in Vertebrates

In eukaryotes, the three families of ATP-dependent DNA ligases are associated with specific functions in DNA metabolism. DNA ligase I (LigI) catalyzes Okazaki-fragment ligation at the replication fork and nucleotide excision repair (NER). DNA ligase IV (LigIV) mediates repair of DNA double strand breaks (DSB) via non-homologous end-joining (NHEJ). The evolutionary younger DNA ligase III (LigIII) is restricted to higher eukaryotes and has been associated with base excision (BER) and single strand break repair (SSBR). We show that in vertebrate DT40 cells, in the absence of LigI, LigIII efficiently supports semi-conservative DNA replication via an alternative DNA replication pathway, as well as NER. LigIII also supports an alternative, low efficiency, NHEJ process that operates as backup to LigIV-dependent NHEJ. Together with its exclusive and essential function in mitochondria, these observations elevate LigIII to a universal ligase, equipped to substitute or backup the functions of all other DNA ligases.