Phillip B. Carpenter, Ph.D.
1994, University of Illinois
UT-Houston Medical School
Biochemistry and Molecular Biology
|
Phillip B. Carpenter, Ph.D. 1994, University of Illinois UT-Houston Medical School |
Research Interests: DNA damage response and genomic stability: Models for lymphoma and other cancer
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 as well as in the T and B cells of the immune system during the processes of V(D)J recombination and class switch recombination (CSR). 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. 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 "histone code." 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 investigated the role of 53BP1 in the repair of double stranded breaks of B cells. B cells normally perform V(D)J and CS recombination to generate diverse antibodies. In the absence of 53BP1, B cells cannot perform CSR, indicating that the animals are immunedeficient and defective in DNA repair. Our studies with 53BP1 in B cells has revealed some important principles for how 53BP1 may operate during the DNA damage response. Moreover, we have evidence that links 53BP1 to lymphomagenesis in both mouse and human model systems.
See related web site at http://www.uth.tmc.edu/bmb/program/programfac/Carpenter/Carpenter.html
____________
Manis, J.P. Morales, J.C., Xia, Z., Kutok, J., Alt, F.W., and Carpenter, P.B. (2004) 53BP1 links DNA damage response pathways to immunoglobulin heavy chain class switch recombination. Nature Immunology. Published online 4-11-04 (see additional commentary on this paper at: Posey et al. Nature Immunology (2004) 5, 476-477.)
Morales JC, et al (2002) Role for the BRCT Protein 53BP1 in Genomic Stability. J. Biol. Chem. 278, 14971-14977.
Fernandez-Capetillo O, et al (2002) DNA-Damage Induced G2/M Checkpoint Activation by Histone H2AX and 53BPI. Nature Cell Biology. 12, 993-997.
Wang B, Matsuoka S, Carpenter PB, Elledge SJ (2002) 53BP1, A Mediator of the DNA Damage Checkpoint. Science. 298:1435-1438.
Ritchie CT, Peterson C, Lu T, Hittelman UN, Carpenter PB, Legerski R (2002) hSnml Colocalizes and Physically Associates with 53BP1 Before and After DNA Damage. Mol.Cell. Biol. 22:8756-8762.
Xia Z, Morales JC, Dunphy WG, Carpenter PB (2001) Negative Cell Cycle Regulation and DNA-Damage Inducible Phosphorylation of the BRCT Protein 53BP1. J. Biol. Chem. 276:2708-2718.
Program Affiliation:
Program in Biochemistry and Molecular
Biology