Cell Cycle Control/DNA Damage Response Networks

The survival of an organism is critically dependent upon the faithful replication (S-phase) and segregation (M-phase) of its chromosomes to daughter cells as the failure to do so may result in cell death or lead to diseases such as cancer through the propagation of genetic mutations. Such survival is dependent upon the ability of the cell to respond to non-spontaneous as well as spontaneous forms of DNA damage. Such types of spontaneous damage occur during each and every cell cycle, particularly in S-phase. It is well established that the failure to repair damaged DNA within the context of the cell cycle can promote tumor formation through the propagation of damaged DNA to daughter cells at mitosis. Indeed, mutations in a number of genes responsible for coordinating DNA damage responses and/or cell cycle processes are frequently found in a variety of cancers. This includes deficiencies in the ATM kinase (ataxia telangiectasia), p53 (Li Fraumeni), Chk2 (Li Fraumeni), and BRCA1 (Breast Cancer 1 susceptibility gene). How BRCA1 functions in the DNA damage response and why mutations in the gene primarily contribute to breast cancer in females has been the subject of much attention and is complicated by the fact that the protein performs multiple functions in the cell cycle, DNA repair, transcription, and even in X-chromosome inactivation. ATM, Chk2, p53, and BRCA1 have well documented roles in the genesis of cases of breast cancer.

Our lab has identified the p53-binding protein 1 (53BP1) as a major player in the response to various types of DNA damage, with particular emphasis on DNA double-stranded breaks.  53BP1, like BRCA1, contains two C-terminal "BRCT" motifs. Such elements have been identified in a number of DNA damage response/cell cycle proteins and are the subject of a great deal of interest given their role in genomic stability. 53BP1 interacts with p53, ATM, and Chk2, all of which have been implicated in breast cancer. We have shown that 53BP1 is phosphorylated in response to DNA damage by a variety of kinases including ATM and that this event correlates with its rapid re-localization to sites of DNA damage (see below). 53BP1 is recruited to these sites of DNA damage by a variant of histone2A, known as H2AX. This histone variant is involved in DNA repair and in cell cycle checkpoints and serves as the DNA damage version of the Òhistone codeÓ. How 53BP1 influences the function of BRCA1 and other DNA damage response factors like Chk2 and p53 and whether this is related to its tumor suppression activity are currently being investigated in this lab. We have determined that 53BP1 is absolutely required for the process of Òclass switch recombination (CSR)Ó, a DNA recombination event that is integral to the development of the immune system.  Thus, in the absence of functional 53BP1, knock-out mice generated in this lab display immune deficiencies as a result of their failure to properly conduct DNA repair at the switch loci.  Such persistent breaks in DNA are well known to serve as oncogenic lesions.  Moreover, these animals, when examined under the appropriate genetic background, are highly susceptible to developing B and T cell lymphomas.

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