Abstract
To maintain genomic stability and ensure the fidelity of chromosomal transmission, cells respond to various forms of genotoxic stress, including DNA double-stranded breaks (DSBs), through the activation of DNA damage response signaling networks. In response to DSBs as induced by ionizing radiation (IR), during DNA replication, or through immunoglobulin heavy chain (IgH) rearrangements in B cells of lymphoid origin, the phosphatidyl inositol-like kinase (PIK) kinases ATM (mutated in ataxia telangiectasia), ATR (ATM and Rad3-related kinase), and the DNA-dependent protein kinase (DNA-PK) activate signaling pathways that lead to DSB repair. DSBs are repaired by either of two major, non-mutually exclusive pathways: homologous recombination (HR) that utilizes an undamaged sister chromatid template (or homologous chromosome) and non- homologous end joining (NHEJ), an error prone mechanism that processes and joins broken DNA ends through the coordinated effort of a small set of ubiquitous factors (DNA-PKcs, Ku70, Ku80, artemis, Xrcc4/DNA lig IV, and XLF/Cernunnos). The PIK kinases phosphorylate a variety of effector substrates that propagate the DNA damage signal, ultimately resulting in various biological outputs that influence cell cycle arrest, transcription, DNA repair, and apoptosis. A variety of data has revealed a critical role for p53-binding protein 1 (53BP1) in the cellular response to DSBs including various aspects of p53 function. Importantly, 53BP1 plays a major role in suppressing translocations, particularly in B and T cells. This report will review past experiments and current knowledge regarding the role of 53BP1 in the DNA damage response.
Highlights
The p53 gene encodes a tumor suppressor whose primary function is in transcription. p53 is inactivated or disrupted in ≥50% of all human cancers
Human 53BP1 is comprised of 1,972 residues and contains important structural elements including two Breast Cancer Gene 1 (BRCA1) C-terminal (BRCT) repeats, tandem Tudor domains, a GAR methylation stretch, two dynein light chain (LC8) binding sites, and numerous phosphatidyl inositol-like kinase (PIK) kinases and cyclin-dependent (CDK) phosphorylation sites (Fig. 1)
This suggested that 53BP1 mediated the DNA damage response by facilitating ATM activity towards at least a subset of its substrates and raised the possibility that 53BP1 could function in ATM activation, an event that is likely to be tightly coupled to chromatin structure and function [11,29]
Summary
The p53 gene encodes a tumor suppressor whose primary function is in transcription. p53 is inactivated or disrupted in ≥50% of all human cancers. One study showed that 53BP1-/- cells had a prolonged G2 phase, a phenotype reported in ATM-deficient cells [30] This suggested that 53BP1 mediated the DNA damage response by facilitating ATM activity towards at least a subset of its substrates and raised the possibility that 53BP1 could function in ATM activation, an event that is likely to be tightly coupled to chromatin structure and function [11,29]. ChIP analysis reveals that phosphorylated H2A in budding yeast is not associated with the break per se, but rather the Mre complex appears to localize to sites of DNA damage [34] This is believed to contribute, at least in part, to ATM activation http://www.celldiv.com/content/1/1/19
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