DNA ligase III

Abstract

Lig1 and Lig4 are found throughout eukaryotes. Lig1 is considered to be the critical ligase during replication of the nuclear genome, while Lig4 is critical for the repair of double-strand breaks (DSBs) by nonhomologous end joining (NHEJ). Lig3 has been implicated both in nuclear DNA repair and in mitochondrial genome maintenance.3,4 Although Lig3 has a more restricted phylogenetic distribution in eukaryotes than the other two ligases, it is found more broadly in eukaryotic groups than originally thought, as will be discussed below. Lig3 is Essential for Cellular Viability due to its Role in MitochondriaRecent work using both cell complementation and tissue-specific deletion in the animal has shed light on the role of Lig3.5-7 Lig3-null mouse embryos die at ~8.5 dpc and previous attempts to generate Lig3-null cells were unsuccessful, 8 suggesting that Lig3 is required for cell survival. To directly determine whether Lig3 is an essential gene in cells, we developed a pre-emptive complementation strategy in mouse embryonic stem (ES) cells (Fig. 1)

DNA ligase III and DNA ligase IV carry out genetically distinct forms of end joining in human somatic cells

“…It has interchangeably been referred to as MMEJ (micro-homology-mediated end joining) [9], B-NHEJ (backup-NHEJ) [10] and A-NHEJ (alternative-NHEJ) [11], {hereafter, A-NHEJ}. Unlike the HR and C-NHEJ pathways, which are conserved from bacteria to man, the A-NHEJ pathway has evolved in a somewhat checkered manner and can only be detected in about a third of eukaryotic genomes [12]. It is presumed that an end-binding factor besides Ku is required to bind onto the broken DNA ends, stabilize them, protect them from random nuclease degradation and finally funnel the ends into the A-NHEJ pathway [13].…”

“…In particular, a brute-force nuclear extract fractionation protocol identified LIGIII {DNA ligase III; [12]}, heretofore known only for its role in BER (base excision repair), as the candidate ligase required for A-NHEJ [16]. Using guilt-by-association as a scientific rationale, PARP1 {poly (ADP-ribose) polymerase 1} and XRCC1 (X-ray cross complementing gene 1), two proteins known to interact with LIGIII during BER, were subsequently identified as also being involved in A-NHEJ [13, 17, 18].…”

“…Unlike the other ligases, LIGIII is molecularly heterogeneous [12, 36, 37]. Thus, alternative translation initiation generates mitochondrial and nuclear forms of LIGIII, which either contain or lack a MLS (mitochondrial localizing sequence), respectively [36].…”

Structure and function of the DNA ligases encoded by the mammalian LIG3 gene

“…Initially, it was thought that the LIG3 gene was restricted to vertebrates but, with the sequencing of more genomes, it has now been found in about 30% of eukaryotes, including members of 4 of the 6 ancestral eukaryotic groups (Simsek and Jasin, 2011). This distribution suggests that the LIG3 gene arose relatively early during the evolution of eukaryotes but was not always retained.…”

“…As eukaryotes became more complex, it was presumably advantageous to have multiple LIG genes that encoded a broader repertoire of DNA ligases to participate in the increasing number of specialized DNA transactions, including immunoglobulin gene rearrangements in immune cells, meiosis and germ cell development, the use of poly (ADP-ribose) to signal DNA damage and the different DNA repair pathways in proliferating and terminally differentiated cells. Notably, the DNA ligases encoded by vertebrate LIG3 genes have acquired several conserved accessory domains that flank the core catalytic region during evolution (Simsek and Jasin, 2011). As discussed below, these domains play critical roles in dictating the multiple cellular functions of the DNA ligases encoded by the LIG3 gene in vertebrate DNA metabolism.…”