Elg1 (Enhanced level of genome instability 1) has an essential role in early development and suppressing tumorigenesis

Abstract

IntroductionHigh 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 is a suppressor of genomic instability and functions in DNA repair in yeast and human.ObjectivesTo investigate whether the loss of Elg1 in mouse a in vivo model system causes any genomic disorder and null Elg1 MEF cells shows any Genomic instability phenotypes.ResultsAbsence of Elg1 in mice caused early embryonic lethality and zebra fish Elg1 MO embryos also has developmental problem suggesting Elg1 has an essential role during early development. This embryonic developmental defect rescued in absence of p53 in zebrafish and developed normal. The heterozygous mice developed tumors including sarcoma, carcinoma, and adenoma in various organs from 11 month after birth. The Elg1+/mMEFs and Elg1+/− chicken DT 40 cells show high level of DN A damage sensitivity as well as chromosomal instability in respond to DNA damage. High levels of genomic rearrangements were observed in tumors developed in the Elg1+/mmice 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.ConclusionsTaken together, Elg1 has an essential role in early development that appears to have a close link to suppress genomic instability and ultimately tumorigenesis.