Jul 5, 2018
Video: Franziska Bleichert and her group
Sep 6, 2017
Three FMI group leaders awarded prestigious European Research Council Grant
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Molecular mechanisms of DNA replication and chromosome maintenance
Cellular life depends on the faithful propagation of genetic information. Prior to cell division, a host of different proteins work in concert to duplicate genomes by semi-conservative replication in a manner that preserves relative gene copy numbers and allows for the segregation of copied chromosomes into daughter cells.
To sustain genome integrity, DNA replication must be highly efficient and accurate, with approximately two light years-worth of DNA synthesized during the lifespan of a human being and an error rate of less than 1 per 100 million incorporated bases. This robustness is remarkable considering that the DNA substrate for the replication machinery is packaged into chromatin within the crowded nuclear environment of eukaryotic cells, and it necessitates that DNA replication is temporally and spatially tightly coupled to chromatin remodeling events. How chromatin environment controls key DNA replication events, however, remains poorly understood.
Our research program is focused on uncovering molecular mechanisms by which the nuclear chromatin landscape impacts different steps of DNA replication. We use an integrated mix of biochemical, biophysical, and structural methods (single-particle cryo-electron microscopy and X-ray crystallography) to identify and visualize key chromatin-associated replication intermediates at atomic or near-atomic resolution. In combination with in vivo genetic approaches, our efforts will help not only to establish molecular models for how the likely complex interplay between chromatin structure and DNA replication contributes to maintaining chromosome copy number and genome stability, but also to generate mechanistic frameworks for how deregulation of these events contributes to human disease.
This is a list of selected publications from this group. For a full list of publications, please visit our Publications page and search by group name.
Bleichert F, Botchan MR, Berger JM (2017) Mechanisms for initiating cellular DNA replicationScience. 355 pii: eaah6317
Nodelman IM, Bleichert F, Patel A, Ren R, Horvath KC, Berger JM, Bowman GD (2017) Interdomain communication of the Chd1 chromatin remodeler across the DNA gyres of the nucleosomeMol Cell. 65:447-459
Bleichert F, Botchan MR, Berger JM (2015) Crystal structure of the eukaryotic origin recognition complexNature. 519:321-326
Bleichert F, Balasov M, Chesnokov I, Nogales E, Botchan MR, Berger JM (2013) A Meier-Gorlin syndrome mutation in a conserved C-terminal helix of Orc6 impedes origin recognition complex formationeLife. 2:e00882
Lyubimov AY, Costa A, Bleichert F, Botchan MR, Berger JM (2012) ATP-dependent conformational dynamics underlie the functional asymmetry of the replicative helicase from a minimalist eukaryoteProc Natl Acad Sci USA. 109:11999-12004
Bleichert F, Gagnon KT, Brown II BA, Maxwell ES, Leschziner AE, Unger VM, Baserga SJ (2009) A dimeric structure for archaeal box C/D small ribonucleoproteinsScience. 325:1384-1387
Bleichert F, Granneman S, Osheim YN, Beyer AL, Baserga SJ. (2006) The PINc domain protein Utp24, a putative nuclease, is required for the early cleavage steps in 18S rRNA maturationProc Natl Acad Sci USA. 103:9464-9469
Full list of publications
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