Ku, originally identified as the autoantigen associated with systemic lupus erythematosus (1), is an abundant nuclear protein with fascinating multifunctionality. Ku exists primarily in a heterodimer form composed of ~70 and ~86 kD subunits (referred to as Ku70 and Ku80), which can also form into a larger functional complex, termed the DNA-dependent protein kinase (DNA-PK) complex. In addition to Ku, the DNA-PK complex contains the 470-kD DNA-dependent protein kinase catalytic subunit (DNA-PKcs) (2,3).

Surprisingly, Ku—along with several other proteins that play critical roles in double-stranded break repair through the nonhomologous end-joining (NHEJ) pathway or during site-specific recombination of V(D)J gene segments—recently has been shown to play additional roles in capping telomeres or preventing chromosome end fusions (4-10). Therefore, Ku can function in seemingly opposite ways—either joining DNA ends or preventing telomeric fusions—depending on its nuclear context or microenvironment. Ku also has been reported to play critical roles during transcriptional regulation and in modulation of chromatin structure (11-17).

This chapter will focus primarily on the role of Ku at the telomere. Current understanding of the role Ku plays at the telomere has come mainly from yeast and mammalian studies. Ku has been shown to function in telomeric capping (or in preventing telomere end fusions), telomeric DNA length control, and telomeric silencing. Ku is known to interact with certain telomeric proteins in yeast and mammals (see details below), although the exact role that Ku plays at the telomere and how it localizes to the telomere are not presently known. Importantly, despite the

Sequ ence-

indi.1 pendent Ku

DNA end binding

Sequence-dependent DNA/RNA binding

Protei it-protein association

Figure 1 Ku has been observed to form three different types of intermolecular contacts:s (a) sequence-independent DNA end binding, (b) sequence-dependent DNA/RNA binding, and (c) protein-protein associations. These interactions are likely important for its functional role in the cell.

well-known binding affinity of Ku for DNA termini, there is currently no evidence that Ku binds directly to the ends of telomeric DNA in a sequence-independent manner. Furthermore, mammalian Ku does not bind directly to internal regions of telomeric DNA in a sequence-dependent manner (8). It is likely that the telomere is a dynamic structure with various telomeric components forming many different intermolecular interactions, depending on the cell cycle, age of the organism, and other biological conditions. This chapter will explore possible roles for Ku in telomeric maintenance and several possible intermolecular contacts that may facilitate its function.

Before focusing on the telomere, a brief description of Ku protein's intermolecular contacts during other important cellular processes is provided. These background sections are not intended to provide the reader with a complete review of Ku, but are meant to inform the reader of the capabilities and potentials of Ku and provide an understanding of how Ku might function at the telomere. For a more comprehensive summary of Ku, the reader is referred to several excellent reviews (3,18).

Remarkably, three basic types of intermolecular interactions have been assigned to the Ku heterodimer: (a) sequence-independent DNA end binding, (b) sequence-dependent DNA/RNA binding to internal regions of nucleic acids, and (c) protein-protein interactions (Fig. 1). Understanding the basic molecular associations that Ku forms at the telomere is required for a continued understanding of the basic actions of Ku at the telomere.

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