Zinkel Lab

My lab is interested in understanding the mechanisms by which normal and malignant cells regulate programmed cell death or apoptosis following DNA damage.  Multicellular organisms have devised a tightly regulated, genetically programmed mechanism of cell suicide to maintain homeostasis and to prevent propagation of genetically damaged cells.  The discovery of the BCL-2 family of genes uncovered the underlying genetic mechanism of this regulation, as well as an entirely new class of oncogenes: those that govern cell death rather than cell proliferation.

Current studies focus on the pro-death BCL-2 family member BID.  The deletion of BID in mice prolongs the lives of myeloid cells culminating in the development of a fatal disorder resembling the human disease chronic myelomonocytic leukemia (CMML).  Our recent work has shown an additional role for BID in preserving genomic integrity that is distinct from its pro-apoptotic role.  Following DNA damage, BID is phosphorylated by the DNA damage kinase ATM and plays a role in cell cycle checkpoint control.  Cells initiate a complex series of responses subsequent to DNA damage including activation of cell cycle checkpoints, promoting DNA repair, or activating apoptosis.  BID, with its dual function in apoptosis and the DNA damage response, is well situated to serve as a mediator in determining cell fate following DNA damage.

The projects in my lab use hematopoietic cell culture systems, mouse models, immunofluorescence, as well as apoptosis, cell cycle checkpoint and DNA repair assays to understand the signals and protein interactions that direct BID to assume an apoptotic or cell cycle checkpoint/DNA repair role following treatment with agents inducing DNA damage. An additional focus is to dissect the mechanism of Bcl-2 family members in mouse models of leukemia. Our studies provide new insights into the interplay between apoptosis and cell cycle checkpoint/DNA repair responses following DNA damage, and their role in myeloid homeostasis and leukemogenesis.

Publications

Most recent publications

  1. BID binds to replication protein A and stimulates ATR function following replicative stress. Liu Y, Vaithiyalingam S, Shi Q, Chazin WJ, Zinkel SS (2011) Mol Cell Biol 31(21): 4298-309
    › Primary publication · 21859891 (PubMed) · PMC3209332 (PubMed Central)
  2. Proapoptotic Bid mediates the Atr-directed DNA damage response to replicative stress. Liu Y, Bertram CC, Shi Q, Zinkel SS (2011) Cell Death Differ 18(5): 841-52
    › Primary publication · 21113148 (PubMed) · PMC3074003 (PubMed Central)
  3. A role for proapoptotic Bax and Bak in T-cell differentiation and transformation. Biswas S, Shi Q, Matise L, Cleveland S, Dave U, Zinkel S (2010) Blood 116(24): 5237-46
    › Primary publication · 20813900 (PubMed) · PMC3012541 (PubMed Central)
  4. Bid regulates the pathogenesis of neurotropic reovirus. Danthi P, Pruijssers AJ, Berger AK, Holm GH, Zinkel SS, Dermody TS (2010) PLoS Pathog : e1000980
    › Primary publication · 20617182 (PubMed) · PMC2895667 (PubMed Central)
  5. Investigation of the proapoptotic BCL-2 family member bid on the crossroad of the DNA damage response and apoptosis. Zinkel SS (2008) Methods Enzymol : 231-50
    › Primary publication · 18662573 (PubMed)
  6. Bid plays a role in the DNA damage response. Zinkel SS, Hurov KE, Gross A (2007) Cell 130(1): 9-10; author reply 10-1
    › Primary publication · 17632047 (PubMed)
  7. BCL2 family in DNA damage and cell cycle control. Zinkel S, Gross A, Yang E (2006) Cell Death Differ 13(8): 1351-9
    › Primary publication · 16763616 (PubMed)
  8. A role for proapoptotic BID in the DNA-damage response. Zinkel SS, Hurov KE, Ong C, Abtahi FM, Gross A, Korsmeyer SJ (2005) Cell 122(4): 579-91
    › Primary publication · 16122425 (PubMed)
  9. Proapoptotic BID is required for myeloid homeostasis and tumor suppression. Zinkel SS, Ong CC, Ferguson DO, Iwasaki H, Akashi K, Bronson RT, Kutok JL, Alt FW, Korsmeyer SJ (2003) Genes Dev 17(2): 229-39
    › Primary publication · 12533511 (PubMed) · PMC195974 (PubMed Central)
  10. Death and survival signals determine active/inactive conformations of pro-apoptotic BAX, BAD, and BID molecules. Korsmeyer SJ, Gross A, Harada H, Zha J, Wang K, Yin XM, Wei M, Zinkel S (1999) Cold Spring Harb Symp Quant Biol : 343-50
    › Primary publication · 11232306 (PubMed)

Community Leaders

Contact Information

2220 Pierce Ave.
548 PRB
Nashville, TN 37232
USA

No contact person provided

Keywords & MeSH Terms

MeSH terms are retrieved from PubMed records. Learn more.

Key: MeSH Term Keyword

Amino Acid Motifs apoptosis BCL-2 family BID biochemistry cancer Caspase 8 Caspase 9 cell cycle Cell Differentiation Cell Survival Chromatin DNA DNA-Binding Proteins DNA damage response DNA repair Encephalitis, Viral fas Receptor Fibroblasts knockout leukemia Leukemia, Myelomonocytic, Chronic Liver mass spectrometry Models, Biological Molecular Sequence Data mouse Myeloid Progenitor Cells Myeloproliferative Disorders phosphorylation Promoter Regions, Genetic proteomics Recombinant Proteins signal transduction S Phase stem cells