WRN

What is WRN protein?

WRN gene (WRN RecQ like helicase) is a protein coding gene which situated on the short arm of chromosome 8 at locus 8p12. This gene encodes a member of the RecQ subfamily of DNA helicase proteins. The encoded nuclear protein is important in the maintenance of genome stability and plays a role in DNA repair, replication, transcription and telomere maintenance. This protein contains a N-terminal 3' to 5' exonuclease domain, an ATP-dependent helicase domain and RQC (RecQ helicase conserved region) domain in its central region, and a C-terminal HRDC (helicase RNase D C-terminal) domain and nuclear localization signal. The WRN protein is consisted of 1432 amino acids and WRN molecular weight is approximately 162.5 kDa.

What is the function of WRN protein?

WRN has 3' to 5' helicase activity, which means it can unwind DNA in the 3' to 5' direction. This activity is crucial for processes such as DNA replication, repair, and recombination. The protein plays a significant role in several DNA repair pathways, including nucleotide excision repair (NER), base excision repair (BER), and double-strand break repair (DSBR), particularly through the homologous recombination (HR) pathway. WRN is implicated in the maintenance of telomeres, the protective caps at the ends of chromosomes, which is important for preventing genomic instability associated with aging. The protein may have a role in resolving replication fork stalling and collapse, which can occur during DNA synthesis. WRN interacts with a variety of proteins involved in DNA metabolism, including replication factors, repair enzymes, and other helicases.

WRN Related Signaling Pathway

In DNA repair pathways. WRN is related to Nucleotide Excision Repair, Base Excision Repair and Double-Strand Break Repair. WRN is involved in the resolution of replication fork stalling and collapse, which is essential for preventing genomic instability. Also, this protein is implicated in the maintenance and stabilization of telomeres, which protect the ends of chromosomes from degradation. WRN participates in genetic recombination, which is important for generating genetic diversity during meiosis and for the repair of DNA breaks. It has helicase and exonuclease activities that are essential for various DNA metabolic processes, including replication, repair, and recombination. WRN interacts with cell cycle proteins and may be involved in cell cycle checkpoint control, particularly in response to DNA damage.

WRN Related Diseases

Werner Syndrome is a rare genetic disorder caused by a mutation in the WRN gene that causes patients to experience a much faster than normal aging process. Certain variants of the WRN gene may be associated with other forms of presenily-like symptoms that involve physiological changes that accelerate aging. Due to the role of the WRN protein in DNA repair, loss of its function may increase the risk of cancer, especially those types of cancer associated with defective DNA repair. At the same time, it is also associated with other diseases including: cardiovascular disease, diabetes, neurodegenerative diseases.

Fig1. Roadmap towards the use of WRN inhibitors in the clinic. (David A Morales-Juarez, 2022)

Bioapplications of WRN

Due to its role in DNA repair and maintenance of genomic stability, WRN protein may play a role in the development of cancer, so it is an important target for cancer biology research. Functional restoration or activation of WRN proteins may help treat diseases associated with WRN deficiency, such as certain types of cancer and symptoms of premature aging, making WRN a potential target for drug screening and development. The functional correction or supplement of WRN gene may be beneficial for the treatment of diseases caused by WRN gene mutation, which provides a possible application direction for gene therapy.

Case Study 1: Dali Zong, 2023

Addiction to the WRN helicase is a unique vulnerability of human cancers with high levels of microsatellite instability (MSI-H). However, while prolonged loss of WRN ultimately leads to cell death, little is known about how MSI-H cancers initially respond to acute loss of WRN-knowledge. Here, researchers report the construction of an inducible ligand-mediated degradation system in which the stability of endogenous WRN protein can be rapidly and specifically tuned, enabling to track the complete sequence of cellular events elicited by acute loss of WRN function. WRN degradation leads to immediate accrual of DNA damage in a replication-dependent manner. As a result, WRN-degraded MSI-H cancer cells accumulate DNA damage across multiple replicative cycles and undergo successive rounds of increasingly aberrant mitoses, ultimately triggering cell death. Under conditions of partial WRN degradation, addition of low-dose ATR inhibitor significantly increased their combined efficacy to levels approaching full inactivation of WRN.

Fig1. Targeting strategy to achieve knock-in of FKBP-WRN at the endogenous human WRN locus.

Fig2. Immunoblotting of dTAG-treated RKO FKBP-WRN cells.

Case Study 2: Venkateswarlu Popuri, 2010

NEIL1, the mammalian homolog of Escherichia coli endonuclease VIII, is a DNA glycosylase that repairs ring-fragmented purines, saturated pyrimidines and several oxidative lesions like 5-hydroxyuracil, 5-hydroxycytosine, etc. Previous studies from our laboratory have shown that Werner Syndrome protein (WRN), one of the five human RecQ helicases, stimulates NEIL1 DNA glycosylase activity on oxidative DNA lesions. The goal of this study was to extend this observation and analyze the interaction between NEIL1 and all five human RecQ helicases. The DNA substrate specificity of the interaction between WRN and NEIL1 was also analyzed. The results indicate that WRN is the only human RecQ helicase that stimulates NEIL1 DNA glycosylase activity, and that this stimulation requires a double-stranded DNA substrate.

Fig3. Stimulation of NEIL1 incision activity on duplex substrate with FapyA lesions specifically by WRN.

Fig4. WRN can't stimulate NEIL2.

WRN has several biochemical functions, for example, 3-5 DNA helicase activity,3-5 exonuclease activity,ATP binding. Some of the functions are cooperated with other proteins, some of the functions could acted by WRN itself. We selected most functions WRN had, and list some proteins which have the same functions with WRN. You can find most of the proteins on our site.

WRN has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with WRN here. Most of them are supplied by our site. Hope this information will be useful for your research of WRN.

XRCC5;XRCC6;RPA1