DNA ligase 3

Last updated

LIG3
PDB 1imo EBI.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases LIG3 , LIG2, DNA ligase 3, LIG3alpha, MTDPS20
External IDs OMIM: 600940; MGI: 109152; HomoloGene: 32109; GeneCards: LIG3; OMA:LIG3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3980

16882

Ensembl

ENSG00000005156

ENSMUSG00000020697

UniProt

P49916

P97386

RefSeq (mRNA)

NM_002311
NM_013975

NM_001291245
NM_001291246
NM_001291247
NM_010716

RefSeq (protein)

NP_002302
NP_039269

n/a

Location (UCSC) Chr 17: 34.98 – 35.01 Mb Chr 11: 82.67 – 82.7 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

DNA ligase 3 also DNA ligase III, is an enzyme that, in humans, is encoded by the LIG3 gene. [5] [6] LIG3 encodes ATP-dependent DNA ligases that seal interruptions in the phosphodiester backbone of duplex DNA.

Contents

There are three families of ATP-dependent DNA ligases in eukaryotes. [7] These enzymes utilize the same three step reaction mechanism; (i) formation of a covalent enzyme-adenylate intermediate; (ii) transfer of the adenylate group to the 5' phosphate terminus of a DNA nick; (iii) phosphodiester bond formation. Unlike LIG1 and LIG4 family members that are found in almost all eukaryotes, LIG3 family members are less widely distributed. [8] LIG3 encodes several distinct DNA ligase species by alternative translation initiation and alternative splicing mechanisms that are described below.

Structure, DNA binding and catalytic activities

Eukaryotic ATP-dependent DNA ligases have related catalytic region that contains three domains, a DNA binding domain, an adenylation domain and an oligonucleotide / oligosaccharide binding-fold domain. When these enzymes engage a nick in duplex DNA, these domains encircle the DNA duplex with each one making contact with the DNA. The structure of the catalytic region of DNA ligase III complexed with a nicked DNA has been determined by X-ray crystallography and is remarkably similar to that formed by the catalytic region of human DNA ligase I bound to nicked DNA. [9] A unique feature of the DNA ligases encoded by the LIG3 gene is an N-terminal zinc finger that resembles the two zinc fingers at the N-terminus of poly (ADP-ribose) polymerase 1 (PARP1). [10] As with the PARP1 zinc fingers, the DNA ligase III zinc finger is involved in binding to DNA strand breaks. [10] [11] [12] Within the DNA ligase III polypeptide, the zinc finger co-operates with the DNA binding domain to form a DNA binding module. [13] In addition, the adenylation domain and an oligonucleotide/oligosaccharide binding-fold domain form a second DNA binding module. [13] In the jackknife model proposed by the Ellenberger laboratory, [13] the zinc finger-DNA binding domain module serves as a strand break sensor that binds to DNA single strand interruptions irrespective of the nature of the strand break termini. If these breaks are ligatable, they are transferred to the adenylation domain-oligonucleotide/oligosaccharide binding-fold domain module that binds specifically to ligatable nicks. Compared with DNA ligases I and IV, DNA ligase III is the most active enzyme in the intermolecular joining of DNA duplexes. [14] This activity is predominantly dependent upon the DNA ligase III zinc finger suggesting that the two DNA binding modules of DNA ligase III may be able to simultaneously engage duplex DNA ends. [9] [13]

Alternative splicing

The alternative translation initiation and splicing mechanisms alter the amino- and carboxy-terminal sequences that flank the DNA ligase III catalytic region. [15] [16] In the alternative splicing mechanism, the exon encoding a C-terminal breast cancer susceptibility protein 1 C-terminal (BRCT) domain at the C-terminus of DNA ligase III-alpha is replaced by a short positively charged sequence that acts as a nuclear localization signal, generating DNA ligase III-beta. This alternatively spliced variant has, to date, only been detected in male germs cells. [16] Based on its expression pattern during spermatogenesis, it appears likely that DNA ligase IIIbeta is involved in meiotic recombination and/or DNA repair in haploid sperm but this has not been definitively demonstrated. Although an internal ATG is the preferred site for translation initiation within the DNA ligase III open reading frame, translation initiations does also occur at the first ATG within the open reading frame, resulting in the synthesis of a polypeptide with an N-terminal mitochondrial targeting sequence. [15] [17] [18]

Cellular function

As mentioned above, DNA ligase III-alpha mRNA encodes nuclear and mitochondrial versions of DNA ligase III-alpha. Nuclear DNA ligase III-alpha exists and functions in a stable complex with the DNA repair protein XRCC1. [19] [20] These proteins interact via their C-terminal BRCT domains. [16] [21] XRCC1 has no enzymatic activity but instead appears to acts as a scaffold protein by interacting with a large number of proteins involved in base excision and single-strand break repair. The participation of XRCC1 in these pathways is consistent with the phenotype of xrcc1 cells. [19] In contrast to nuclear DNA ligase III-alpha, mitochondrial DNA ligase III-alpha functions independently of XRCC1, which is not found in mitochondria. [22] It appears that nuclear DNA ligase III-alpha forms a complex with XRCC1 in the cytoplasm and the subsequent nuclear targeting of the resultant complex is directed by the XRCC1 nuclear localization signal. [23] While mitochondrial DNA ligase III-alpha also interacts with XRCC1, it is likely that the activity of the mitochondrial targeting sequence of DNA ligase III-alpha is greater than the activity of the XRCC1 nuclear localization signal and that the DNA ligase III-alpha/XRCC1 complex is disrupted when mitochondrial DNA ligase III-alpha passes through the mitochondrial membrane.

Since the LIG3 gene encodes the only DNA ligase in mitochondria, inactivation of the LIG3 gene results in loss of mitochondrial DNA that in turn leads to loss of mitochondrial function. [24] [25] [26] Fibroblasts with inactivated Lig3 gene can be propagated in the media supplemented with uridine and pyruvate. However, these cells lack mtDNA. [27] Physiological levels of mitochondrial DNA ligase III appear excessive, and cells with 100-fold reduced mitochondrial content of mitochondrial DNA ligase III-alpha maintain normal mtDNA copy number. [27] The essential role of DNA ligase III-alpha in mitochondrial DNA metabolism can be fulfilled by other DNA ligases, including the NAD-dependent DNA ligase of E. coli , if they are targeted to mitochondria. [24] [26] Thus, viable cells that lack nuclear DNA ligase III-alpha can be generated. While DNA ligase I is the predominant enzyme that joins Okazaki fragments during DNA replication, it is now evident that the DNA ligase III-alpha/XRCC1 complex enables cells that either lack or have reduced DNA ligase I activity to complete DNA replication. [24] [26] [28] [29] Given the biochemical and cell biology studies linking the DNA ligase III-alpha/XRCC1 complex with excision repair and the repair of DNA single strand breaks, [30] [31] [32] it was surprising that the cells lacking nuclear DNA ligase III-alpha did not exhibit significantly increased sensitivity to DNA damaging agent. [24] [26] These studies suggest that there is significant functional redundancy between DNA ligase I and DNA ligase III-alpha in these nuclear DNA repair pathways. In mammalian cells, most DNA double strand breaks are repaired by DNA ligase IV-dependent non-homologous end joining (NHEJ). [33] DNA ligase III-alpha participates in a minor alternative NHEJ pathway that generates chromosomal translocations. [34] [35] Unlike the other nuclear DNA repair functions, it appears that the role of DNA ligase III-alpha in alternative NHEJ is independent of XRCC1. [36]

Clinical significance

Unlike the LIG1 and LIG4 genes, [37] [38] [39] [40] inherited mutations in the LIG3 gene have not been identified in the human population. DNA ligase III-alpha has, however, been indirectly implicated in cancer and neurodegenerative diseases. In cancer, DNA ligase III-alpha is frequently overexpressed and this serves as a biomarker to identify cells that are more dependent upon the alternative NHEJ pathway for the repair of DNA double strand breaks. [41] [42] [43] [44] Although the increased activity of the alternative NHEJ pathway causes genomic instability that drives disease progression, it also constitutes a novel target for the development of cancer cell-specific therapeutic strategies. [42] [43] Several genes encoding proteins that interact directly with DNA ligase III-alpha or indirectly via interactions with XRCC1 have been identified as being mutated in inherited neurodegenerative diseases. [45] [46] [47] [48] [49] Thus, it appears that DNA transactions involving DNA ligase III-alpha play an important role in maintaining the viability of neuronal cells.

LIG3 has a role in microhomology-mediated end joining (MMEJ) repair of double strand breaks. It is one of 6 enzymes required for this error prone DNA repair pathway. [50] LIG3 is upregulated in chronic myeloid leukemia, [44] multiple myeloma, [51] and breast cancer. [42]

Cancers are very often deficient in expression of one or more DNA repair genes, but over-expression of a DNA repair gene is less usual in cancer. For instance, at least 36 DNA repair enzymes, when mutationally defective in germ line cells, cause increased risk of cancer (hereditary cancer syndromes).[ citation needed ] (Also see DNA repair-deficiency disorder.) Similarly, at least 12 DNA repair genes have frequently been found to be epigenetically repressed in one or more cancers.[ citation needed ] (See also Epigenetically reduced DNA repair and cancer.) Ordinarily, deficient expression of a DNA repair enzyme results in increased un-repaired DNA damages which, through replication errors (translesion synthesis), lead to mutations and cancer. However, LIG3 mediated MMEJ repair is highly inaccurate, so in this case, over-expression, rather than under-expression, apparently leads to cancer.

Notes

Related Research Articles

<span class="mw-page-title-main">DNA ligase</span> Class of enzymes

DNA ligase is a type of enzyme that facilitates the joining of DNA strands together by catalyzing the formation of a phosphodiester bond. It plays a role in repairing single-strand breaks in duplex DNA in living organisms, but some forms may specifically repair double-strand breaks. Single-strand breaks are repaired by DNA ligase using the complementary strand of the double helix as a template, with DNA ligase creating the final phosphodiester bond to fully repair the DNA.

<span class="mw-page-title-main">DNA polymerase</span> Form of DNA replication

A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create two identical DNA duplexes from a single original DNA duplex. During this process, DNA polymerase "reads" the existing DNA strands to create two new strands that match the existing ones. These enzymes catalyze the chemical reaction

<span class="mw-page-title-main">Ubiquitin ligase</span> Protein

A ubiquitin ligase is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate. In simple and more general terms, the ligase enables movement of ubiquitin from a ubiquitin carrier to another thing by some mechanism. The ubiquitin, once it reaches its destination, ends up being attached by an isopeptide bond to a lysine residue, which is part of the target protein. E3 ligases interact with both the target protein and the E2 enzyme, and so impart substrate specificity to the E2. Commonly, E3s polyubiquitinate their substrate with Lys48-linked chains of ubiquitin, targeting the substrate for destruction by the proteasome. However, many other types of linkages are possible and alter a protein's activity, interactions, or localization. Ubiquitination by E3 ligases regulates diverse areas such as cell trafficking, DNA repair, and signaling and is of profound importance in cell biology. E3 ligases are also key players in cell cycle control, mediating the degradation of cyclins, as well as cyclin dependent kinase inhibitor proteins. The human genome encodes over 600 putative E3 ligases, allowing for tremendous diversity in substrates.

<span class="mw-page-title-main">Poly (ADP-ribose) polymerase</span> Family of proteins

Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes such as DNA repair, genomic stability, and programmed cell death.

<span class="mw-page-title-main">Base excision repair</span> DNA repair process

Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from the genome. The related nucleotide excision repair pathway repairs bulky helix-distorting lesions. BER is important for removing damaged bases that could otherwise cause mutations by mispairing or lead to breaks in DNA during replication. BER is initiated by DNA glycosylases, which recognize and remove specific damaged or inappropriate bases, forming AP sites. These are then cleaved by an AP endonuclease. The resulting single-strand break can then be processed by either short-patch or long-patch BER.

<span class="mw-page-title-main">Chromosome 2</span> Human chromosome

Chromosome 2 is one of the twenty-three pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 2 is the second-largest human chromosome, spanning more than 242 million base pairs and representing almost eight percent of the total DNA in human cells.

<span class="mw-page-title-main">MUTYH</span> Protein-coding gene in the species Homo sapiens

MUTYH is a human gene that encodes a DNA glycosylase, MUTYH glycosylase. It is involved in oxidative DNA damage repair and is part of the base excision repair pathway. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a common form of oxidative DNA damage.

<span class="mw-page-title-main">Protein inhibitor of activated STAT</span>

Protein inhibitor of activated STAT (PIAS), also known as E3 SUMO-protein ligase PIAS, is a protein that regulates transcription in mammals. PIAS proteins act as transcriptional co-regulators with at least 60 different proteins in order to either activate or repress transcription. The transcription factors STAT, NF-κB, p73, and p53 are among the many proteins that PIAS interacts with.

<span class="mw-page-title-main">XRCC1</span> Protein

DNA repair protein XRCC1, also known as X-ray repair cross-complementing protein 1, is a protein that in humans is encoded by the XRCC1 gene. XRCC1 is involved in DNA repair, where it complexes with DNA ligase III.

<span class="mw-page-title-main">DNA repair protein XRCC4</span> Protein found in humans

DNA repair protein XRCC4 (hXRCC4) also known as X-ray repair cross-complementing protein 4 is a protein that in humans is encoded by the XRCC4 gene. XRCC4 is also expressed in many other animals, fungi and plants. hXRCC4 is one of several core proteins involved in the non-homologous end joining (NHEJ) pathway to repair DNA double strand breaks (DSBs).

<span class="mw-page-title-main">MRE11A</span> Protein-coding gene in the species Homo sapiens

Double-strand break repair protein MRE11 is an enzyme that in humans is encoded by the MRE11 gene. The gene has been designated MRE11A to distinguish it from the pseudogene MRE11B that is nowadays named MRE11P1.

<span class="mw-page-title-main">DNA ligase 4</span> Enzyme found in humans

DNA ligase 4 also DNA ligase IV, is an enzyme that in humans is encoded by the LIG4 gene.

<span class="mw-page-title-main">DNA ligase 1</span> Protein-coding gene in the species Homo sapiens

DNA ligase 1 also DNA ligase I, is an enzyme that in humans is encoded by the LIG1 gene. DNA ligase 1 is the only known eukaryotic DNA ligase involved in both DNA replication and repair, making it the most studied of the ligases.

<span class="mw-page-title-main">DNA polymerase beta</span> Protein-coding gene in the species Homo sapiens

DNA polymerase beta, also known as POLB, is an enzyme present in eukaryotes. In humans, it is encoded by the POLB gene.

<span class="mw-page-title-main">Flap structure-specific endonuclease 1</span> Protein-coding gene in the species Homo sapiens

Flap endonuclease 1 is an enzyme that in humans is encoded by the FEN1 gene.

<span class="mw-page-title-main">Aprataxin</span> Protein-coding gene in the species Homo sapiens

Aprataxin is a protein that in humans is encoded by the APTX gene.

<span class="mw-page-title-main">ERCC4</span> Protein-coding gene in the species Homo sapiens

ERCC4 is a protein designated as DNA repair endonuclease XPF that in humans is encoded by the ERCC4 gene. Together with ERCC1, ERCC4 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.

<span class="mw-page-title-main">DUT (gene)</span> Protein-coding gene in the species Homo sapiens

DUTP pyrophosphatase, also known as DUT, is an enzyme which in humans is encoded by the DUT gene on chromosome 15.

<span class="mw-page-title-main">PNKP</span> Protein-coding gene in the species Homo sapiens

Bifunctional polynucleotide phosphatase/kinase is an enzyme that in humans is encoded by the PNKP gene. A detailed structural study of the crystallized mouse protein examined both the 5´-polynucleotide kinase and 3’-polynucleotide phosphatase activities. Additional features of the peptide sequence include a forkhead association (FHA) domain, ATP binding site and nuclear and mitochondrial localization sequences.

<span class="mw-page-title-main">Single-stranded binding protein</span>

Single-stranded binding proteins (SSBs) are a class of proteins that have been identified in both viruses and organisms from bacteria to humans.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000020697 – Ensembl, May 2017
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