Chapter One - The Repair and Signaling Responses to DNA Double-Strand Breaks
Introduction
A first review entitled DNA Breakage and Repair for Advances in Genetics was written in 1998. At this time, the major focus was to describe and discuss the relatively newly identified genes encoding proteins that function in the major DNA double-strand break (DSB) repair pathway: DNA nonhomologous end-joining (NHEJ). This was an exciting time in the field with the emerging notion that the major DSB repair pathway in mammalian cells was distinct to homologous recombination (HR), the process predominantly exploited by lower organisms, gaining credence as the NHEJ genes were identified. Additionally, an unanticipated role for NHEJ during V(D)J recombination, a critical process in development of the immune response which rearranges and rejoins the subexon components of the immunoglobulin and T cell receptor genes, had been newly revealed. Thus, understanding the NHEJ process was of interest not just to those workers in the DNA damage response (DDR) field but additionally to immunologists. Now in 2013, together with Aaron Goodarzi, we venture to revisit this area. Although distinct to earlier years, the field remains dynamic, rapidly advancing, and exciting. We now have substantial insight into the basic processes of NHEJ and HR at a structural and biochemical level and a sound appreciation of their cellular roles. Moreover, a recently described process of Alternative-NHEJ (Alt-NHEJ) has been identified. The significance of DSB signal transduction responses has gained credence and insight into the process and its impact on the DDR is slowly emerging. Critical current questions are: how these responses interface, how they are influenced by chromatin structure, and how chromatin is changed to optimally promote DSB repair and avoid genomic instability? Most provocatively, how does the malfunction of these processes lead to chromosomal translocations and rearrangements? The field is substantially broader and more complex than in 1998, making the task of providing an overview more challenging. Here, we aim to provide a description of our current understanding of the DSB repair processes, the signaling response, the interplay between them and other metabolic processes involving DNA, and the impact of, and changes to, the chromatin environment.
Section snippets
Formation of DSBs
There is increasing recognition that the route by which a DSB arises strongly influences the pathway governing its repair. DSBs can arise in a developmentally programmed manner (such as V(D)J recombination, class switch recombination (CSR), or meiosis), following replication fork arrest or stalling, from endogenously arising DNA damage or from exogenous DNA-damaging agents such as ionizing radiation (IR). Each process produces DSBs of a distinctive nature (summarized in Figure 1.1). DSBs that
Mechanisms of DSB Rejoining
HR and NHEJ represent the two major DSB repair pathways; additionally, less well-understood processes have also been described.
DNA Damage Response Signaling
In addition to repair mechanisms, DSBs activate a signal transduction process that drives a range of cellular consequences. Ataxia telangiectasia mutated (ATM) protein lies at the core of the DSB signaling response although in certain circumstances (e.g., following DSB end resection or if DSBs become encountered at the replication fork), ataxia telangiectasia mutated and Rad3 related (ATR) can also trigger a signaling-related cascade. Several outstanding reviews on the choreography of DSB
Functions of the DDR Assembly
Ataxia telangiectasia (A-T), the human disorder caused by ATM mutation, is one of the most radiosensitive human conditions, demonstrating the importance of ATM signaling to the DSB response (Jeggo & Lavin, 2009). Studies of chromosomal breakage in A-T cells revealed increased persisting chromosome breaks (Jeggo & Lavin, 2009). However, DSB repair analysis assessed using procedures such as pulsed field gel electrophoresis (PFGE) or the rate of loss of the DSB marker, γH2AX, revealed nearly
Impact of cell cycle phase and resection
There is increasing evidence that the choice between DSB repair pathways is highly regulated and represents a significant function of IRIF assembly. Since HR is argued to be a more accurate DSB repair process and functions only in late S/G2, it was widely assumed that HR would represent the major DSB repair pathway in G2 phase (see below). However, studies focusing on the analysis of irradiated G2 cells (and inhibition of the progression of irradiated S phase cells into G2) have shown that, in
Contribution of Defects in DSB Rejoining Processes to Human Disease
Given the role of NHEJ in V(D)J recombination, a striking and expected phenotype of mice lacking NHEJ proteins is severe combined immunodeficiency (SCID). Mutations in NHEJ proteins (DNA ligase IV, XLF, Artemis, and DNA-PKcs) have now been identified in a subclass of SCID or CID patients, defined as radiosensitive-SCID (RS-SCID) (O'Driscoll et al., 2001, O'Driscoll and Jeggo, 2006). Such patients undergo bone marrow transplantation (BMT) frequently, and the identification of such patients is
Concluding Remarks
Here, we have overviewed the dramatic changes that arise as a consequence of DSB formation and consider how these changes impact upon the DSB repair process. Studies using lower organisms predicted that HR would represent the major DSB repair pathway in mammalian cells. However, it is increasingly evident that NHEJ carries out repair of most DSBs with HR functioning predominantly to handle lesions, including one-ended DSBs, at replication forks. One consideration underlying the greater
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