Accession Number : AD1018895


Title :   Control of Colon Cancer Progression by the Colon Microbiome


Descriptive Note : Technical Report,15 Jul 2014,14 Jul 2015


Corporate Author : The Wistar Institute of Anatomy and Biology Philadelphia United States


Personal Author(s) : Rauscher,Frank III J


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1018895.pdf


Report Date : 01 Aug 2015


Pagination or Media Count : 20


Abstract : This Research Project was funded to define the roles of bacterial pathogen proteins which modify host proteins by post-translational modification. We have made great progress in accomplishing all of the AIMS of this project. The NF-B pathwayis most critical for immune defense against infection, thereby frequently targeted by bacterial virulence effectors. NleE, aneffector from EPEC and related enteric bacteria, is a SAM-dependent methyltransferase that blocks host NF-B-mediatedinflammation. We have solved the crystal structure of NleE-SAM complex, which reveals a methyltransferase fold differentfrom those of known methyltransferases. We further identify a new NleE substrate: ZRANB3, which has well defined roles inPCNA binding and remodeling of stalled replication forks at sites of DNA damage. NleE-catalyzed cysteine methylation of theZRANB3-NZF domain also abolishes its K63-linked ubiquitin chain-binding activity, a key modification of PCNA which initiatesrepair. Specific inactivation of the NZF domain in ZRANB3 by NleE, and hence its DNA repair functions suggests a novel andunexpected link between EPEC infection, virulence proteins and genome integrity. We have also discovered a new NleE substrate: ZRANB1/ Trabid1 , which contains three target zinc fingers and differentially methylates these three fingers tomodulate binding to mixed ubiquitin linked chains. Trabid1 functions in the NF-kB pathway in innate immunity like TAB2/3.


Descriptors :   colon cancer , infectious diseases , receptor sites (physiology) , Escherichia coli , cell physiological processes , cultured cells , amino acids , recombinant proteins , bacterial proteins , transcription factors , wound infections , Deoxyribonucleic acids , Transferases


Distribution Statement : APPROVED FOR PUBLIC RELEASE