BBS Faculty Member - Johannes Walter

Johannes Walter

Howard Hughes Medical Institute
Department of Biological Chemistry and Molecular Pharmacology


Harvard Medical School
Seeley G Mudd Building, Room 204A
240 Longwood Ave.
Boston, MA 02115
Tel: 617-432-4799
Fax: 617-738-0516
Email: johannes_walter@hms.harvard.edu
Lab Members: 9 postdoctoral fellows, 4 graduate students, 1 undergraduate student
Visit my lab page here.



Vertebrate cells employ elaborate mechanisms to faithfully duplicate their genomes and guard against DNA damage. Xenopus laevis frog egg extracts have an extraordinary capacity to recapitulate these processes in the test tube, allowing us to elucidate the underlying mechanisms. We are working on the following areas:

1. DNA cross-link repair. Our cells are constantly exposed to reactive compounds (e.g. endogenous aldehydes) that covalently link the two strands of DNA to each other, thus generating highly toxic inter-strand crosslinks (ICLs). The same compounds also covalently cross-link proteins to DNA, generating DNA protein cross-links (DPCs). While defects in ICL repair cause bonre marrow failure and cancer, defective DPC repair appears to cause premature aging and liver cancer. We have recapitulated ICL and DPC repair in egg extracts and find that in both cases, repair is triggered when a DNA replication fork collides with the damage (Raschle et al., Cell 2008; Duxin et al., Cell 2014). We are now studying how ICLs and DPCs are repaired in the context of replication and how defects in these repair reactions cause disease.

2. Single molecule studies of double-strand break repair. We have shown that DNA replication can be studied at the single molecule level in frog egg extracts (Yardimci et al., Molecular Cell, 2010; Fu et al., Cell 2011; Kochaniak et al., Nature Methods, 2012). We are now using this approach to examine how DNA double strands breaks are repaired via homologous recombination and non-homologous end joining (in collaboration with BBS faculty member Joe Loparo).

3. Replication termination. What happens when two DNA replication forks converge at the end of replication: how is DNA synthesis completed and how is the replication machinery disassembled? We recently recapitulated site-specific replication termination in egg extracts, leading to a new and unexpected model of this process (Dewar et al., Nature, 2015). We are now using this approach to elucidate how removal of the replication machinery is regulated by the ubiquitin system.



Last Update: 8/11/2015



Publications

For a complete listing of publications click here.

 


 

Dewar, J.D., Budzowska, M., Walter, J.C. (2015). The mechanism of DNA replication termination in vertebrates. Nature, in press.

Duxin, J.P., Dewar, J.M., Yardimci, H., and
Walter, J.C. (2014). Replication-coupled repair of a DNA-protein crosslink. Cell 159, 346-357. PMC4229047

Knipscheer, P., Räschle, M., Smogorzewska, A., Enoiu, M., Ho, T.V., Schärer, O.D., Elledge, S.J., and
Walter, J.C. (2009). The Fanconi anemia pathway promotes replication-dependent DNA interstrand crosslink repair. Science 326, 1698-1701. PMCID: PMC2909596



© 2015 by the President and Fellows of Harvard College