The role of WRNIP1 in genome maintenance

Abstract

WRNIP1 interacts with WRN helicase, which is defective in the premature aging disease Werner syndrome. WRNIP1 belongs to the AAA+ ATPase family and is conserved from Escherichia coli to human. The protein contains an ubiquitin-binding zinc finger (UBZ) domain at the N terminus and an ATPase domain in the middle region. In addition to WRN, WRNIP1 interacts with proteins involved in multiple cellular pathways, including RAD18, monoubiquitylated PCNA, DNA polymerase δ, RAD51, and ATMIN. Mgs1, the yeast homolog of WRNIP1, may act downstream of ubiquitylation of PCNA to mobilize DNA polymerase δ. By contrast, the functions of WRNIP1 in higher eukaryotic cells remain obscure, although data regarding the roles of WRNIP1 in DNA transactions have emerged recently. Here, we first describe the functions of Mgs1 in DNA transaction. We then describe various features of WRNIP1 and discuss its possible roles based on recent studies of the function of WRNIP1.

Keywords: ATMIN; DNA polymerase δ; DNA polymerase η; Mgs1; PCNA; RAD18; WRN; WRNIP1; ubiquitin.

Figure 1.

Schematic showing the functional domains of WRNIP1. The sequence of the Rad18-like ubiquitin-binding zinc finger (UBZ) within WRNIP1 is aligned with those of RAD18, Polκ, and Mgs1, and that of polη UBZ. Zinc ion-coordinating residues are denoted by blue letters. RAD18-like CCHC zinc fingers are denoted by red letters.

Figure 2.

Possible roles of Mgs1 and WRNIP1 in DNA transaction. A. Role of Mgs1. PCNA plays the important role in regulating the DNA damage tolerance pathway via its modification with ubiquitin and SUMO in yeast. SUMOylated PCNA interacts with Srs2 helicase, which prevents homologous recombination by disrupting DNA-Rad51 filaments. The 2 types of ubiquitylated PCNA (monoubiquitylated PCNA and polyubiquitylated PCNA) channels the lesion bypass to translesion synthesis and template switch, respectively. Mgs1 induces polymerase switch from Polδ to Polη during TLS. Mgs1 may also act in the template switch. *This pathway is essential when the RAD6 pathway and homologous recombination are disabled. B. Role of WRNIP1. WRNIP1 stabilizes RAD51 nucleofilaments formed by BRCA2, by counteracting FBH1 and protects replication forks from nucleolytic degradation by MRE11. WRNIP1 induces polymerase switch from Polδ to Polη during TLS. WRNIP1 links ubiquitylated PCNA with ATMIN/ATM to activate ATM signaling in response to replication stress.