Structure and function of the DNA ligases encoded by the mammalian LIG3 gene |
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| Authors: | Alan E. Tomkinson Annahita Sallmyr |
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| Affiliation: | Department of Internal Medicine and University of New Mexico Cancer Center, University of New Mexico, Albuquerque, NM 87131, USA |
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| Abstract: | Among the mammalian genes encoding DNA ligases (LIG), the LIG3 gene is unique in that it encodes multiple DNA ligase polypeptides with different cellular functions. Notably, this nuclear gene encodes the only mitochondrial DNA ligase and so is essential for this organelle. In the nucleus, there is significant functional redundancy between DNA ligase IIIα and DNA ligase I in excision repair. In addition, DNA ligase IIIα is essential for DNA replication in the absence of the replicative DNA ligase, DNA ligase I. DNA ligase IIIα is a component of an alternative non-homologous end joining (NHEJ) pathway for DNA double-strand break (DSB) repair that is more active when the major DNA ligase IV-dependent pathway is defective. Unlike its other nuclear functions, the role of DNA ligase IIIα in alternative NHEJ is independent of its nuclear partner protein, X-ray repair cross-complementing protein 1 (XRCC1). DNA ligase IIIα is frequently overexpressed in cancer cells, acting as a biomarker for increased dependence upon alternative NHEJ for DSB repair and it is a promising novel therapeutic target. |
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| Keywords: | BRCT, breast cancer susceptibility protein 1-related C-terminal DBD, DNA binding domain DNA PK, DNA-dependent protein kinase DSB, DNA double-strand break LIG, DNA ligase encoding gene MLS, mitochondrial leader sequence NEIL, Nei endonoclease VIII-like protein NHEJ, non-homologous end joining NLS, nuclear localization signal NTase, nucleotidyl transferase domain OBD, oligonucleotide/oligosaccharide-fold binding domain PARP1, poly(ADP-ribose) polymerase 1 PNKP, polynucleotide kinase phosphatase SSB, DNA single-strand break Tdp1, tyrosyl phosphodiesterase 1 XRCC1, X-ray cross-complementing protein 1 ZnF, zinc finger |
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