Werner syndrome ATP-dependent helicase

Werner syndrome, RecQ helicase-like
250px Structure of DNA- and protein- binding motif of Werner protein. PDB rendering based on 2axl.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2AXL, 2DGZ, 2E1E, 2E1F, 2FBT, 2FBV, 2FBX, 2FBY, 2FC0, 3AAF
Identifiers
Symbols	WRN ; RECQ3; RECQL2; RECQL3
External IDs	OMIM: 604611 MGI: 109635 HomoloGene: 6659 GeneCards: WRN Gene
EC number	3.6.4.12
Gene ontology Molecular function • magnesium ion binding • Y-form DNA binding • bubble DNA binding • DNA binding • DNA helicase activity • ATP-dependent DNA helicase activity • helicase activity • exonuclease activity • protein binding • ATP binding • 3'-5' exonuclease activity • four-way junction helicase activity • ATPase activity • manganese ion binding • protein complex binding • protein homodimerization activity • 3'-5' DNA helicase activity • ATP-dependent 3'-5' DNA helicase activity • G-quadruplex DNA binding Cellular component • nucleoplasm • nucleolus • centrosome • MutLalpha complex Biological process • telomere maintenance • DNA synthesis involved in DNA repair • replicative cell aging • DNA metabolic process • DNA replication • base-excision repair • double-strand break repair • DNA recombination • cellular response to DNA damage stimulus • response to oxidative stress • aging • cell aging • cellular response to starvation • response to UV-C • multicellular organismal aging • protein sumoylation • replication fork processing • nucleolus to nucleoplasm transport • DNA duplex unwinding • regulation of growth rate • regulation of apoptotic process • post-translational protein modification • cellular protein metabolic process • positive regulation of hydrolase activity • cellular response to gamma radiation • nucleic acid phosphodiester bond hydrolysis Sources: Amigo / QuickGO
RNA expression pattern
File:PBB GE WRN 205667 at tn.png
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	7486	22427
Ensembl	ENSG00000165392	ENSMUSG00000031583
UniProt	Q14191	O09053
RefSeq (mRNA)	NM_000553	NM_001122822
RefSeq (protein)	NP_000544	NP_001116294
Location (UCSC)	Chr 8: 31.03 – 31.17 Mb	Chr 8: 33.23 – 33.39 Mb
PubMed search	[1]	[2]

Werner syndrome ATP-dependent helicase also known as DNA helicase, RecQ-like type 3 is an enzyme that in humans is encoded by the WRN gene. WRN is a member of the RecQ Helicase family. Helicase enzymes generally unwind and separate double-stranded DNA. These activities are necessary before DNA can be copied in preparation for cell division (DNA replication). Helicase enzymes are also critical for making a blueprint of a gene for protein production, a process called transcription. Further evidence suggests that Werner protein plays a critical role in repairing DNA. Overall, this protein helps maintain the structure and integrity of a person's DNA.

The WRN gene is located on the short (p) arm of chromosome 8 between positions 12 and 11.2, from base pair 31,010,319 to base pair 31,150,818.

Structure and function

WRN is a member of the RecQ Helicase family. It is the only RecQ Helicase that contains 3' to 5' exonuclease activity. These exonuclease activities include degradation of recessed 3' ends and initiation of DNA degradation from a gap in dsDNA. WRN is important in reparation of double stranded breaks, nonhomologous end joining, and base excision repair. WRN may also be important in telomere maintenance and replication, especially the replication of the G-rich sequences.

WRN is an oligomer that can act as a monomer when unwinding DNA, but as a dimer in solution or a tetramer when complexed with DNA, and has also been observed in tetrameric and hexameric forms. The diffusion of WRN has been measured to 1.62 $\tfrac{\mathrm{\mu m}^2}{\mathrm{s}}$ in nucleoplasm and 0.12 $\textstyle \tfrac{\mathrm{\mu m}^2}{\mathrm{s}}$ at nucleoli. Orthologs of WRN have been found in a number of other organisms, including Drosohphila, Xenopus, and C. elegans. WRN is important to genome stability, and cells with mutations to WRN are more susceptible to DNA damage and DNA breaks.

The amino terminus of WRN is involved in both helicase and nuclease activities, while the carboxyl-terminus interacts with p53, an important tumor suppressor. WRN may function as an exonuclease in DNA repair, recombination, or replication, as well as resolution of DNA secondary structures. It is involved in branch migration at Holliday junctions, and it interacts with other DNA replication intermediates. mRNA that codes for WRN has been identified in most human tissues.

Post-translational modification

Phosphorylation of WRN at serine/threonine inhibits helicase and exonuclease activities which are important to post-replication DNA repair. De-phosphorylation at these sites enhances the catalytic activities of WRN. Phosphorylation may affect other post-translational modifications, including sumoylation and acetylation.

Methylation of WRN causes the gene to turn off. This suppresses the production of the WRN protein and its functions in DNA repair.

Clinical significance

Werner syndrome is caused by mutations in the WRN gene. More than 20 mutations in the WRN gene are known to cause Werner syndrome. Many of these mutations result in an abnormally shortened Werner protein. Evidence suggests that the altered protein is not transported into the cell nucleus, where it normally interacts with DNA. This shortened protein may also be broken down too quickly, leading to a loss of Werner protein in the cell. Without normal Werner protein in the nucleus, cells cannot perform the tasks of DNA replication, repair, and transcription. Researchers are still determining how these mutations cause the appearance of premature aging seen in Werner syndrome.

Interactions

Werner syndrome ATP-dependent helicase has been shown to interact with:

• BLM
• DNA-PKcs,
• FEN1,
• Ku70,
• Ku80,
• P53,
• PCNA,
• TERF2, and
• WRNIP1.

External links

• In
• GeneCard
• Werner Syndrome Mutational Database