br As mentioned above defects in the DNA ligase
As mentioned above, defects in the DNA ligase IIIα-interacting protein TDP1 have been identified as the cause of the hereditary neurodegenerative disease, spinocerebellar ataxia with axonal neuropathy 1 (El-Khamisy et al., 2005). In addition, defects in two other DNA repair proteins, aprataxin and polynucleotide kinase phosphatase (PNKP), that interact with the DNA ligase IIIα:XRCC1 complex have been identified as the causes of ataxia–oculomotor apraxia 1 (Ahel et al., 2006, Moreira et al., 2001) and a recently discovered disease characterized by microcephaly, early onset-intractable seizures and developmental delay (Shen et al., 2010), respectively. TDP1, aprataxin and PNKP are all involved in the cleaning up of termini at SSBs both in nuclei and mitochondria (Das et al., 2010, Mandal et al., 2012, Rass et al., 2007, Sykora et al., 2011, Tahbaz et al., 2012). Aprataxin removes adenylate groups from 5′ phosphate DNA termini, generated by abortive ligation (Ahel et al., 2006) whereas PNKP phosphorylates 5′ hydroxyl termini and dephosphorylates 3′-phosphate termini (Karimi-Busheri and Weinfeld, 1997, Karimi-Busheri et al., 1998). These studies suggest that AG-14361 of the nervous system are more sensitive to the loss of proteins involved in the repair of single strand breaks than other cell types. This may be because terminally differentiated neuronal cells lack some of the DNA repair mechanisms that are active in proliferating cells and/or because of the high levels of active oxidative metabolism in the CNS that generate excessive DNA damage (Barzilai, 2007, Chen et al., 2007). Interestingly, neural-specific inactivation of the XRCC1 and LIG3 genes has different effects on the developing nervous system (Katyal and McKinnon, 2011, Lee et al., 2009). Neuronal cells lacking XRCC1 are hypersensitive to DNA damaging agents that generate SSBs as are neuronal cells lacking either Tdp1 or aprataxin. However, the neuropathology resulting from the loss of XRCC1 function is more severe than that caused by the loss of either Tdp1 or aprataxin. This presumably reflects the central role of XRCC1 in the repair of all nuclear SSBs whereas Tdp1 and aprataxin are only required for specific subsets of SSBs. These studies are consistent with the conclusion that DNA ligase I is the predominant activity in the XRCC1-dependent repair of SSBs in nuclear DNA (Gao et al., 2011). While neural inactivation of XRCC1 resulted in a seizure-like phenotype after about 3months, neural inactivation of LIG3 had a more severe effect, with ataxia evident after two weeks and death within three weeks. The neuropathology induced by the loss of DNA ligase IIIα function was markedly different than that induced by the loss of XRCC1 with the neuronal cells lacking DNA ligase IIIα exhibiting mitochondrial defects. Thus, it appears that XRCC1-dependent repair of nuclear SSBs plays a critical neuroprotective role whereas neuropathologies associated with the loss of DNA ligase IIIα function are due to mitochondrial dysfunction (Katyal and McKinnon, 2011). While the contribution of DNA ligase IIIα to nuclear DNA metabolism may vary depending on cell-type and growth status, it plays an essential and unique role in mitochondrial DNA metabolism. It is possible that the neuropathology resulting from defects in Tdp1, aprataxin or PNKP may be due, at least in part, to reduced DNA ligase IIIα-dependent repair of mitochondrial DNA.
Concluding remarks The mammalian LIG3 gene encodes distinct DNA ligase polypeptides that participate in nuclear and mitochondrial DNA metabolism. Recent studies have shown that the LIG3 gene is essential for cell viability because mitochondrial DNA ligase IIIα is required for mitochondrial function. There is a significant functional redundancy between DNA ligases I and IIIα in nuclear DNA replication and repair. Further studies are needed to characterize the role of DNA ligase IIIα in DNA replication in cells that are deficient in DNA ligase I activity. DNA ligase IIIα is the predominant activity involved in generating chromosomal translocation via its participation in an alternative NHEJ pathway. Notably, DNA ligase III is frequently overexpressed in a significant fraction of cancer cells, resulting in increased activity of the alternative NHEJ pathway. Initial studies with DNA ligase III inhibitors indicate that cancer cells with this DNA repair abnormality can be selectively targeted. Further studies are needed to elucidate the role of DNA ligase IIIβ, which is generated by an alternative splicing mechanism detected in male germ cells, in meiotic recombination and/or germ cell development.