Werner Syndrome Protein and DNA Replication

Abstract

Werner Syndrome (WS) is an autosomal recessive disorder characterized by the premature development of aging features. Individuals with WS also have a greater predisposition to rare cancers that are mesenchymal in origin. Werner Syndrome Protein (WRN), the protein mutated in WS, is unique among RecQ family proteins in that it possesses exonuclease and 3′ to 5′ helicase activities. WRN forms dynamic sub-complexes with different factors involved in DNA replication, recombination and repair. WRN binding partners either facilitate its DNA metabolic activities or utilize it to execute their specific functions. Furthermore, WRN is phosphorylated by multiple kinases, including Ataxia telangiectasia mutated, Ataxia telangiectasia and Rad3 related, c-Abl, Cyclin-dependent kinase 1 and DNA-dependent protein kinase catalytic subunit, in response to genotoxic stress. These post-translational modifications are critical for WRN to function properly in DNA repair, replication and recombination. Accumulating evidence suggests that WRN plays a crucial role in one or more genome stability maintenance pathways, through which it suppresses cancer and premature aging. Among its many functions, WRN helps in replication fork progression, facilitates the repair of stalled replication forks and DNA double-strand breaks associated with replication forks, and blocks nuclease-mediated excessive processing of replication forks. In this review, we specifically focus on human WRN’s contribution to replication fork processing for maintaining genome stability and suppressing premature aging. Understanding WRN’s molecular role in timely and faithful DNA replication will further advance our understanding of the pathophysiology of WS.

Immunomodulatory Effects of Radiotherapy

“…Cyclic GMP-AMP synthase (cGAS) is one of the most important DNA sensors that detects cytosolic DNA and triggers the expression of inflammatory genes that activate defense mechanisms. Tumor-derived DNA, such as micronuclei, DNA of dead tumor cells, cytoplasmic fragments, and free telomeric DNA, can activate the cGAS pathway and induce cellular senescence and antitumor immunity [88,[114][115][116][117][118][119][120][121]. The progression of the cell cycle through mitosis after RT-induced DNA DSBs leads to the formation of micronuclei, cytoplasmic aggregates of damaged DNA encircled by a defective nuclear envelope.…”

Werner Syndrome Protein (WRN) Regulates Cell Proliferation and the Human Papillomavirus 16 Life Cycle during Epithelial Differentiation

“…WRN has 3′ to 5′ exonuclease and helicase activity and is involved in multiple DNA damage and repair processes, including nonhomologous end joining ( 31 – 34 ). However, it is also involved in HR and replication, and since this is the process used by E1-E2 to replicate the viral genome, the role of WRN in viral replication is to promote HR ( 32 , 35 – 42 ). In the absence of SIRT1, E1-E2 replication has a reduced fidelity, and one reason for this could be the lack of WRN recruitment to the replicating DNA ( 26 ).…”

Protective Mechanisms Against DNA Replication Stress in the Nervous System

“…Werner syndrome (OMIM 277700) is a rare autosomal recessive progeroid disorder in which patients exhibit accelerated aging, bilateral cataracts, diabetes mellitus, osteoporosis, and a predisposition to rare cancers [127,128]. Although a neurological disease is not a classical feature of Werner's syndrome patients, brain atrophy (~40% of the patients), altered memory, and neuropathies were reported [129,130] (Table 1).…”