Navigation

Navigation
CONTACT US:


The Department of Biochemistry & Biophysics
UNC School of Medicine
120 Mason Farm Road
Genetic Medicine, Ste 3010
Campux Box #7260
Chapel Hill, NC 27599-7260

Office: (919) 962-8326
Fax: (919) 966-2852

You are here: Home > Dale Ramsden, PhD
Document Actions

Dale Ramsden, PhD

RAMSDEN - Dale

Associate Professor
PhD: University of Toronto

32-044 Lineberger Cancer Ctr
Campus Box 7295
Chapel Hill, NC 27599

919.966.9839 (off)
919.966.9673 (fax)
dale_ramsden@med.unc.edu

RamsdenResIntFig.gif

 

Getting by with less. During NHEJ, polymerases can get by without an intact template partly by replacing it with "loop1." Shown are the increasingly larger loop1s in 4 related human DNA polymerases implicated in NHEJ. The longer the loop, the better the polymerase is in dealing with the absence of a template.

 
RESEARCH INTERESTS:

 
V(D)J Recombination And Double Strand Break Repair

Non-homologous end-joining (NHEJ, end joining) pathway has an important role in all cell types repairing chromosomes with double strand breaks. NHEJ is also essential for efficient resolution of chromosome break intermediates during V(D)J recombination, a lymphocyte specific process required for assembly of the immune system’s antigen specific receptors. We use diverse molecular biological approaches in an effort to understand both how end joining works and why it sometimes does not.

 

NHEJ is unique among DNA repair pathways in that it attempts repair without an intact template to instruct accurate replacement of damaged DNA. We’ve shown you use at least three different DNA polymerases, each with varying dependency on an intact template, to get around this problem. We are continuing to work with Dr. Kunkel’s group at NIEHS to understand the structural basis for different template dependencies.

Given the problems NHEJ faces with accuracy, we are also working to understand why, outside of V(D)J recombination, you’d risk doing NHEJ at all.  We are testing the following ideas: (unlike alternate repair pathways)…

1) NHEJ is fast and cheap: it doesn’t need to do much DNA synthesis. This might explain why NHEJ is most important in non-dividing/slowly dividing cells, where synthesis can’t be easily done.


2) NHEJ does not involve disruption of a lot of adjacent chromatin, allowing you to keep the epigenetic information stored in the chromatin near breaks intact. In contrast, alternate pathways involve extensive nucleosome remodeling, and even nucleosome eviction.

 

We’re also interested in how V(D)J recombination makes the mistakes that lead to lymphoid malignancy. V(D)J recombination involves the popping out of a large segment of your receptor locus, and the mechanism by which you pop this segment out is similar to the way transposons move around their host genomes. We’ve recently shown that the similarity to transposition does not end with the “popping out” step: like transposition, the enzymes responsible for excising DNA segments during V(D)J recombination also re-integrate the excised DNA into some other location in your genome. Is the target for re-integration random? Might re-integration explain the origin of some lymphoid malignancies?

 

 

ramsdengraphic1.jpg

Map of mouse genome with aberrant recombination sites
marked by triangles; red triangles denote transpositions.

 

RECENT PUBLICATIONS:


DeRose EF, Clarkson MW, Gilmore SA, Galban CJ, Tripathy A, Havener JM, Mueller GA, Ramsden DA, London RE, Lee AL. Solution structure of polymerase mu's BRCT Domain reveals an element essential for its role in nonhomologous end joining. Biochemistry. 2007 Oct 30;46(43):12100-10. Epub 2007

 

Povirk LF, Zhou RZ, Ramsden DA, Lees-Miller SP, Valerie K. Phosphorylation in the serine/threonine 2609-2647 cluster promotes but is not essential for DNA-dependent protein kinase-mediated nonhomologous end joining in human whole-cell extracts. Nucleic Acids Res. 2007;35(12):3869-78. Epub 2007

 

Roberts SA, Ramsden DA. Loading of the nonhomologous end joining factor, Ku, on protein-occluded DNA ends. J Biol Chem. 2007 Apr;282(14):10605-13. Epub 2007

 

Moon AF, Garcia-Diaz M, Bebenek K, Davis BJ, Zhong X, Ramsden DA, Kunkel TA, Pedersen LC. Structural insight into the substrate specificity of DNA Polymerase mu. Nat Struct Mol Biol. 2007 Jan;14(1):45-53. Epub 2006
 

Reddy YV, Perkins EJ, Ramsden DA. Genomic instability due to V(D)J recombination-associated transposition. Genes Dev. 2006 Jun 15;20(12):1575-82

Calendar
« November 2008 »
Su Mo Tu We Th Fr Sa
1
234 5678
91011 12131415
161718 19202122
232425 26272829
30
2008 FALL SEMINARS

Tuesdays @ 11:00 am 
408 Mary Ellen Jones
 

 
Site-wide Actions
Personal tools