Roles of Werner syndrome protein in protection of genome integrity

Abstract

Werner syndrome protein (WRN) is one of a family of five human RecQ helicases implicated in the maintenance of genome stability. The conserved RecQ family also includes RecQ1, Bloom syndrome protein (BLM), RecQ4, and RecQ5 in humans, as well as Sgs1 in Saccharomyces cerevisiae, Rqh1 in Schizosaccharomyces pombe, and homologs in Caenorhabditis elegans, Xenopus laevis, and Drosophila melanogaster. Defects in three of the RecQ helicases, RecQ4, BLM, and WRN, cause human pathologies linked with cancer predisposition and premature aging. Mutations in the WRN gene are the causative factor of Werner syndrome (WS). WRN is one of the best characterized of the RecQ helicases and is known to have roles in DNA replication and repair, transcription, and telomere maintenance. Studies both in vitro and in vivo indicate that the roles of WRN in a variety of DNA processes are mediated by post-translational modifications, as well as several important protein-protein interactions. In this work, we will summarize some of the early studies on the cellular roles of WRN and highlight the recent findings that shed some light on the link between the protein with its cellular functions and the disease pathology.

Figure 1. Roles of WRN in S-phase at stalled replication forks

A) WRN may participate in repair of double-strand breaks (DSBs) following DNA damage-induced replication fork collapse. Alternatively, WRN may function to regress the fork and allow for synthesis bypass of DNA damage. B) Secondary structures which block DNA polymerases may be resolved by WRN. (See text for details.)

Figure 2. Roles of WRN during DNA repair

Schematic diagram depicting WRN interactions with various repair proteins in multiple pathways following DNA damage. DNA damage leads to post-translational modifications of WRN which may regulate its roles in DNA repair. (See text for details.)

Figure 3. Role of WRN in replication, recombination, and repair processes at telomeres

(See text for details.)

Figure 4. Involvement of RecQ helicases in maintenance of genomic integrity

Association of different RecQ helicases (RecQ1, WRN, BLM, RecQ4, and RecQ5) with replication, base excision repair (BER), double strand break repair (DSBR), transcription, and telomere maintenance has been indicated by arrows. Dotted line indicates probable involvement. Some major physical and/or functional interacting proteins are also shown with each respective RecQ helicase. (See text for additional details and reviews in [–3, 5, 217].)