Department of Biochemistry, Molecular Biology, School of Medicine, University of Maryland, 108 North Greene Street, Baltimore, Maryland 21201, USA
The structure of the 9-1-1 complex (Doré et al., 2009; Sohn and Cho, 2009; Xu et al., 2009) is similar to the sliding clamp proliferating cell nuclear antigen protein (PCNA) (Gulbis et al., 1996; Krishna et al., 1994). Hus1 interacts with Rad9 and Rad1 through its N terminal domain and C terminal domain, respectively. The structure and surface charge distribution of the interdomain connecting loop (IDCL) of Hus1 differs from those of other two subunits (Doré et al., 2009; Sohn and Cho, 2009; Xu et al., 2009). The IDCL of Hus1 contains an N-terminal alpha helix and positive charge cluster. These differences among Hus1, Rad9, and Rad1 may contribute to different binding affinities to their partner proteins. For example, MutY homolog (MYH) has a strong preference to bind Hus1 (Chang and Lu, 2005; Shi et al., 2006).
Recent structural and functional analyses indicate that the Hus1 binding region of MYH adopts a stabilized conformation projecting away from the catalytic domain to form a docking scaffold for Hus1 and binds to Hus1 through electrostatic interaction (Luncsford et al., 2010).
The 9-1-1 complex is required to activate two checkpoint sensors-ATM (ataxia telangiectasia [AT] mutated protein) and ATR (ATM- and Rad3-related protein), which are phosphoinositol phosphate 3 kinase-related kinases (PIKKs) (Zhou and Elledge, 2000). The DNA-bound 9-1-1 complex facilitates ATM- or ATR-mediated phosphorylation of more than 700 proteins including Chk1, Chk2, p53, and BRCA1 (Zhou and Elledge, 2000). Hus1 facilitated phosphorylation of Chk1 kinase is required for the ATR-dependent checkpoint; and regulates S-phase progression, G2/M arrest, and replication fork stabilization (Sancar et al., 2004; Sancar et al., 2004). However, Hus1 is not required for Chk2 phosphorylation in response to certain genotoxins (Weiss et al., 2003).
Besides acting as a DNA damage sensor, the 9-1-1 complex plays an integral role in several DNA repair pathways including base excision repair (BER), mismatch repair (MMR), and nucleotide excision repair (NER) (see figure 2) (Helt et al., 2005).
In the BER pathway, the 9-1-1 complex facilitates and interacts with several DNA glycosylases including MYH (Chang and Lu, 2005; Shi et al., 2006; Chang and Lu, 2005; Shi et al., 2006), 8-oxoG glycosylase (OGG1) (Park et al., 2009), NEIL1 (Guan et al., 2007a), and thymine DNA glycosylase (TDG) (Guan et al., 2007b). The 9-1-1 complex also interacts with and stimulates other BER enzymes including APE1 (Gembka et al., 2007), POLbeta (Toueille et al., 2004), FEN1 (Friedrich-Heineken et al., 2005; Wang et al., 2004a), RPA (Wu et al., 2005), and DNA ligase 1 (Smirnova et al., 2005; Wang et al., 2006a). Thus, the 9-1-1 complex may provide a platform for the assembly and function of the BER machinery (Balakrishnan et al., 2009; Lu et al., 2006). The 9-1-1 complex enhances mismatch repair via direct interaction with mismatch recognition proteins (MSH2/MSH3, MSH2/MSH6, and MLH1/PMS2) (Bai et al., 2010; He et al., 2008). Hus1 interacts with MSH2/MSH3 and MSH2/MSH6, but not with MLH1/PMS2 (Bai et al., 2010; He et al., 2008).
In the NER pathway, interactions between Saccharomyces cerevisiae Rad14 (hXPA homolog) and the checkpoint proteins ScDdc1 (hRad9 homolog) and ScMec3 (hHus1 homolog) have been demonstrated (Giannattasio et al., 2004). Inactivation of NER by knock down of XPA and XPC resulted in a decrease of G1 phase cells that displayed Rad9 foci in response to UV light (Warmerdam et al., 2009). UV light-induced Rad9 foci also colocalized with TopBP1 and gamma-H2AX (Warmerdam et al., 2009).
Hus1 interacts with histone deacetylase HDAC1 (Cai et al., 2000). A novel pathway has been proposed that HDAC1 is involved in G(2)/M checkpoint control through the interaction with the 9-1-1 complex.
Jab1 physically associates with the 9-1-1 complex, causes the translocation of the 9-1-1 complex from the nucleus to the cytoplasm, and mediates the rapid degradation of the 9-1-1 complex (Huang et al., 2007).
NCBI: 3364 MIM: 603760 HGNC: 5309 Ensembl: ENSG00000136273
dbSNP: 3364 ClinVar: 3364 TCGA: ENSG00000136273 COSMIC: HUS1
Amrita Madabushi ; Randall C Gunther ; A-Lien Lu
HUS1 (HUS1 checkpoint homolog (S. pombe))
Atlas Genet Cytogenet Oncol Haematol. 2010-09-01
Online version: http://atlasgeneticsoncology.org/gene/40899/hus1