The sticky business of histone H2AX in V(D)J recombination, maintenance of genomic stability, and suppression of lymphom
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The sticky business of histone H2AX in V(D)J recombination, maintenance of genomic stability, and suppression of lymphoma Bu Yin · Craig H. Bassing
Published online: 12 July 2008 © Springer Science+Business Media, LLC 2008
Abstract DNA double strand breaks (DSBs) induced during cellular metabolism, DNA replication, and genomic rearrangement events lead to phosphorylation of the H2AX core histone variant in surrounding chromatin. H2AX is essential for normal DSB repair, maintenance of genomic stability, and suppression of lymphomas with clonal translocations and intra-chromosomal deletions. One current focus of our lab is to elucidate mechanisms through which H2AX functions in the cellular DNA damage response using V(D)J recombination as a model system. A number of potential H2AX functions can be readily tested using novel experimental approaches developed in our lab. These putative functions include: (1) modulation of chromatin accessibility to facilitate kinetics of DSB repair, (2) stabilization of broken DNA strands to maintain ends in close proximity, and (3) ampliWcation of DNA damage signals. Here, we summarize our recent eVorts in elucidating mechanisms by which H2AX functions during V(D)J recombination to coordinate DSB repair with cellular proliferation and survival to prevent translocations and suppress lymphomagenesis. Keywords Histone H2AX · V(D)J recombination · Double strand breaks · Genomic instability · Chromatin · DNA repair · Cell cycle checkpoints
B. Yin Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA B. Yin · C. H. Bassing (&) Cancer Biology Program, Cell and Molecular Biology Graduate Group, Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 807A Abramson Research Center, 3615 Civic Center Boulevard, Philadelphia, PA 19104-4318, USA e-mail: [email protected]
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Immunol Res (2008) 42:29–40
The cellular responses to DNA double strand breaks DNA double strand breaks (DSBs) are dangerous cellular lesions since broken DNA strands can separate irreversibly or join erroneously. Such genomic instability can lead to cell death or drive malignant transformation. Unfortunately, DSBs are also very common. They arise in every S phase through DNA replication errors and can be induced in any cell cycle phase by exogenous factors such as ionizing radiation (IR) or endogenous factors like reactive oxygen species [1–3]. Despite their hazard, DSBs are a necessary part of DNA biology. For example, induction and repair of DSBs by topoisomerases is required to modulate DNA topology and enable DNA replication in all cells [4]. Moreover, initiation of DSBs by endonucleases at site-speciWc genomic locations is essential for processes such as adaptive immunity in more evolutionarily advanced organisms [5–7]. Consequently, cells have evolved eYcient, specialized, and redundant
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