TY  - JOUR
A1  - Rohleder, Florian
A1  - Huang, Jing
A1  - Xue, Yutong
A1  - Kuper, Jochen
A1  - Round, Adam
A1  - Seidman, Michael
A1  - Wang, Weidong
A1  - Kisker, Caroline
T1  - FANCM interacts with PCNA to promote replication traverse of DNA interstrand crosslinks
JF  - Nucleic Acids Research
N2  - FANCM is a highly conserved DNA remodeling enzyme that promotes the activation of the Fanconi anemia DNA repair pathway and facilitates replication traverse of DNA interstrand crosslinks. However, how FANCM interacts with the replication machinery to promote traverse remains unclear. Here, we show that FANCM and its archaeal homolog Hef from Thermoplasma acidophilum interact with proliferating cell nuclear antigen (PCNA), an essential co-factor for DNA polymerases in both replication and repair. The interaction is mediated through a conserved PIP-box; and in human FANCM, it is strongly stimulated by replication stress. A FANCM variant carrying a mutation in the PIP-box is defective in promoting replication traverse of interstrand crosslinks and is also inefficient in promoting FANCD2 monoubiquitination, a key step of the Fanconi anemia pathway. Our data reveal a conserved interaction mode between FANCM and PCNA during replication stress, and suggest that this interaction is essential for FANCM to aid replication machines to traverse DNA interstrand crosslinks prior to post-replication repair.
KW  - genome integrity
KW  - repair and replication
KW  - FANCM
KW  - proliferating cell nuclear antigen (PCNA)
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-175401
VL  - 44
IS  - 7
ER  - 
TY  - JOUR
A1  - Lorenzin, Francesca
A1  - Benary, Uwe
A1  - Baluapuri, Apoorva
A1  - Walz, Susanne
A1  - Jung, Lisa Anna
A1  - von Eyss, Björn
A1  - Kisker, Caroline
A1  - Wolf, Jana
A1  - Eilers, Martin
A1  - Wolf, Elmar
T1  - Different promoter affinities account for specificity in MYC-dependent gene regulation
JF  - eLife
N2  - Enhanced expression of the MYC transcription factor is observed in the majority of tumors. Two seemingly conflicting models have been proposed for its function: one proposes that MYC enhances expression of all genes, while the other model suggests gene-specific regulation. Here, we have explored the hypothesis that specific gene expression profiles arise since promoters differ in affinity for MYC and high-affinity promoters are fully occupied by physiological levels of MYC. We determined cellular MYC levels and used RNA- and ChIP-sequencing to correlate promoter occupancy with gene expression at different concentrations of MYC. Mathematical modeling showed that binding affinities for interactions of MYC with DNA and with core promoter-bound factors, such as WDR5, are sufficient to explain promoter occupancies observed in vivo. Importantly, promoter affinity stratifies different biological processes that are regulated by MYC, explaining why tumor-specific MYC levels induce specific gene expression programs and alter defined biological properties of cells.
KW  - MYC
KW  - promoter affinity
KW  - human
KW  - mathematical modeling
KW  - mouse
KW  - ChIP-sequencing
KW  - MIZ1
KW  - cancer biology
KW  - cell biology
KW  - WDR5
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-162913
VL  - 5
ER  - 
TY  - JOUR
A1  - Daryaee, Fereidoon
A1  - Chang, Andrew
A1  - Schiebel, Johannes
A1  - Lu, Yang
A1  - Zhang, Zhuo
A1  - Kapilashrami, Kanishk
A1  - Walker, Stephen G.
A1  - Kisker, Caroline
A1  - Sotriffer, Christoph A.
A1  - Fisher, Stewart L.
A1  - Tonge, Peter J.
T1  - Correlating drug-target kinetics and in vivo pharmacodynamics: long residence time inhibitors of the FabI enoyl-ACP reductase
JF  - Chemical Science
N2  - Drug-target kinetics enable time-dependent changes in target engagement to be quantified as a function of drug concentration. When coupled to drug pharmacokinetics (PK), drug-target kinetics can thus be used to predict in vivo pharmacodynamics (PD). Previously we described a mechanistic PK/PD model that successfully predicted the antibacterial activity of an LpxC inhibitor in a model of Pseudomonas aeruginosa infection. In the present work we demonstrate that the same approach can be used to predict the in vivo activity of an enoyl-ACP reductase (FabI) inhibitor in a model of methicillin-resistant Staphylococcus aureus (MRSA) infection. This is significant because the LpxC inhibitors are cidal, whereas the FabI inhibitors are static. In addition P. aeruginosa is a Gram-negative organism whereas MRSA is Gram-positive. Thus this study supports the general applicability of our modeling approach across antibacterial space.
KW  - Staphylococcus aureus
KW  - antibacterial activity
KW  - LpxC inhibitors
KW  - enoyl-ACP reductase inhibitors
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191218
VL  - 7
IS  - 9
ER  -