Poster Sessions

CANCER-9

Nilabja Sikdar

N. Sikdar, R. Chatterjee, H. Park, M. ishiai, G. Elliott, A. Elkahloun, R. Sood, P. Geahart, C. Vinson, M. Takata, D. Lim, K. Myung

Elg1 (Enhanced Level of Genome Instability 1) Has an Essential Role in Early Development and Suppressing Tumorigenesis

High levels of chromosome rearrangements known as gross chromosomal rearrangements (GCRs) such as translocations, deletion of chromosome arm, interstitial deletions, inversions and gene amplification, have been reported in many cancers. Multiple pathways, such as S-phase checkpoints, DNA replication, chromatin remodeling, and telomere maintenance suppress the GCR formation. Elg1 was discovered during the genome wide screening of yeast S. cerevisiae as a suppressor of GCR formation. Elg1 forms an alternative RFC-like complex with RFC2-5 and interacts with proliferating cell nuclear antigen (PCNA) suggesting Elg1-RFC2-5 could function for loading or unloading PCNA. Reduced expression of human ELG1 or the null mutation of yeast ELG1 causes high level of genomic instability. The enhanced PCNA ubiquitination in human cells expressing low level of ELG1, suggested that ELG1 could suppress genomic instability by regulating the homeostasis of ubiquitination in PCNA that determines the post replication repair. Reduced Expression of ELG1 in human shows hudge level of chromosome breakage and higher amount of gamma H2AX, phospho ATM and 53BP1 foci formed in nucleus due to reduced expression of human ELG1. To investigate whether the defect in Elg1 causes any abnormality in vivo, mice having a mutation in Elg1 were generated. The null mutation of Elg1 (Elg1m/m) caused early embryonic lethality (days 8.5 to 9.5 p.c.) and zebra fish Elg1 MO embryos also has developmental problem suggesting Elg1 has an essential role during early development. The Elg1+/m mice developed tumors starting from 11 month after birth. Total 20 mice out of 22 heterozygous mice developed tumors including sarcoma, carcinoma, and adenoma in various organs. These tumors appear to be due to the enhanced genomic instability because the Elg1+/m mice developed high level of genomic instability in vivo and MEFs from the Elg1+/m mice developed high level of DNA damage sensitivity as well as chromosomal instability in respond to DNA damage. Consistently, high levels of genomic rearrangements were observed in tumors developed in the Elg1+/m mice by comparative genome hybridization. The microarray and pathway analysis of tumors from the Elg1 heterozygous mice showed the upregulation of Smad independent Tgf-β pathway. Taken together, Elg1 has an essential role in early development that appears to have a close link to suppress genomic instability and ultimately tumorigenesis.