Structure of the TRFH Dimerization Domain of the Human Telomeric Proteins TRF1 and TRF2 (original) (raw)

apoptosis (Karlseder et al., 1999; van Steensel et al., Hills Road 1998). In general, mammalian cells respond to TRF2 Cambridge CB2 2QH deficiency as if their natural chromosome ends resemble United Kingdom DNA breaks, resulting in degradation of the single-2 The Rockefeller University stranded telomeric overhang, inappropriate ligation of New York, New York 10021 chromosome ends, and activation of the ATM/p53 DNA damage response pathway (Karlseder et al., 1999; van Steensel et al., 1998). Summary Similarly, fission yeast telomeres are protected from end-to-end fusions and recombination by a TRF-related TRF1 and TRF2 are key components of vertebrate teloprotein, Taz1, that binds to duplex telomeric DNA (Fermeres. They bind to double-stranded telomeric DNA reira and Cooper, 2001; Nakamura et al., 1998). Like as homodimers. Dimerization involves the TRF homol-TRF1 and TRF2, Taz1 acts as a negative regulator of ogy (TRFH) domain, which also mediates interactions telomere length (Cooper et al., 1997; Nimmo et al., 1998). with other telomeric proteins. The crystal structures Remarkably, budding yeast lacks a TRF-like telomeric of the dimerization domains from human TRF1 and protein, and in this organism scRap1p is the main factor TRF2 were determined at 2.9 and 2.2 Å resolution, that binds duplex telomeric DNA and regulates telomere respectively. Despite a modest sequence identity, the length (Marcand et al., 1997a; 1997b; McEachern et al., two TRFH domains have the same entirely ␣-helical 2000). architecture, resembling a twisted horseshoe. The di-The TRF family of proteins have similar architectures, merization interfaces feature unique interactions that defined by two sequence features (Figure 1A). First, prevent heterodimerization. Mutational analysis of these proteins have C-terminal DNA binding motifs that TRF1 corroborates the structural data and underare closely related to the Myb domain of c-Myb (Nishiscores the importance of the TRFH domain in dimerkawa et al., 1998; Ogata et al., 1994) and also to the ization, DNA binding, and telomere localization. A pos-Myb/homeodomains of the budding yeast Rap1p (Konig sible structural homology between the TRFH domain et al., 1996; Konig and Rhodes, 1997). Second, these of fission yeast telomeric protein Taz1 with those of proteins have a centrally located sequence motif of the vertebrate TRFs is suggested. about 200 aa, referred to as the TRF homology (TRFH) domain that is unique to this gene family (Broccoli et