Joseph J. Loparo
Harvard University, MA·Biochemistry
When both strands of the DNA double helix snap, the cell faces one of the most dangerous kinds of damage. Even a single double strand break can kill a cell, and faulty repair can rearrange chromosomes, a major driver of cancer.
- Fields
Biochemistry
Biophysics
Genetics
- Topics
DNA double strand break
non-homologous end joining
homologous recombination
- Grants
- 2 known grants, through Jun 2030
What they work on
- Determine how core and accessory non-homologous end joining factors cooperate to tether broken DNA ends, using single-molecule imaging of the synaptic complex in a physiological cell-free system.
- Test how DNA end synapsis is maintained while end-processing enzymes act, and how those enzymes are prioritized to minimize mutagenesis at the repair junction.
- Clarify how Ku, the end-joining factor that antagonizes DNA end resection, is removed from DNA ends, using Xenopus laevis egg extract that recapitulates double strand break pathway choice.
- Examine how the microhomology-mediated end joining polymerase Pol θ competes with long-range resection on partially resected overhangs, and how its multiple enzymatic activities synapse ends and search for microhomology.
More about the research
Cells have several repair pathways, and some of them are error-prone. Both projects ask how the repair machinery holds broken ends together, chooses a pathway, and limits mistakes. They share a toolkit: extracts made from eggs of the frog Xenopus laevis that reproduce repair outside the cell, combined with single-molecule imaging that watches individual repair proteins act on DNA in real time.
Why it matters
Mistakes in rejoining broken chromosomes underlie the genome rearrangements associated with cancer, and overactive end joining helps tumors resist radiation and other DNA-damaging treatments. Deficiencies in these pathways also cause genetic diseases marked by immune deficiency and radiation sensitivity. A mechanistic account of end joining and pathway choice could guide the design of repair inhibitors and may suggest ways to shift the balance between pathways, with potential applications in gene editing and in treating repair-deficient cancers.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Francesca Storici
Georgia Institute of Technology, GA·Genetics
Build matched human kidney (HEK293T) and diploid retinal pigment epithelial (RPE-1) cell lines expressing spliced or non-spliced RNA from the same AAVS1 safe-harbor insertion site, and measure how each transcript changes end-joining repair of CRISPR/Cas9 breaks using deep sequencing.
Joshua Heyza
Wayne State University, MI·Biochemistry·Early-career
Determine what the intrinsically disordered PST repeat domain of MDC1 binds on chromatin and how phosphorylation regulates that tether, using molecular, biochemical and biophysical approaches together with live-cell single-molecule imaging.
Dale A Ramsden
University of North Carolina at Chapel Hill, NC·Biochemistry
Determine how Pol θ's interactions with the DNA-copying machinery, including the polymerase Pol δ and the DNA clamp PCNA, affect cells' need for Pol θ-mediated end joining.
The school
Harvard University: 42 labs on PI Pages, $1.5B a year on research, 712 research doctorates a year.
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