GSBS Student Publications

Title

Rb inactivation leads to E2F1-mediated DNA double-strand break accumulation

UMMS Affiliation

Graduate School of Biomedical Sciences; Department of Molecular Genetics and Microbiology

Date

9-28-2005

Document Type

Article

Medical Subject Headings

Base Sequence; Cell Transformation, Neoplastic; Cells, Cultured; *DNA Damage; E2F1 Transcription Factor; *Genes, Retinoblastoma; Humans; Proto-Oncogene Proteins c-myc; RNA, Small Interfering

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

Although it is unclear which cellular factor(s) is responsible for the genetic instability associated with initiating and sustaining cell transformation, it is known that many cancers have mutations that inactivate the Rb-mediated proliferation pathway. We show here that pRb inactivation and the resultant deregulation of one E2F family member, E2F1, leads to DNA double-strand break (DSB) accumulation in normal diploid human cells. These DSBs occur independent of Atm, p53, caspases, reactive oxygen species, and apoptosis. Moreover, E2F1 does not contribute to c-Myc-associated DSBs, indicating that the DSBs associated with these oncoproteins arise through distinct pathways. We also find E2F1-associated DSBs in an Rb mutated cancer cell line in the absence of an exogenous DSB stimulus. These basal, E2F1-associated DSBs are not observed in a p16(ink4a) inactivated cancer cell line that retains functional pRb, unless pRb is depleted. Thus, Rb status is key to regulating both the proliferation promoting functions associated with E2F and for preventing DNA damage accumulation if E2F1 becomes deregulated. Taken together, these data suggest that loss of Rb creates strong selective pressure, via DSB accumulation, for inactivating p53 mutations and that E2F1 contributes to the genetic instability associated with transformation and tumorigenesis.

Rights and Permissions

Citation: Oncogene. 2006 Feb 2;25(5):746-55. Link to article on publisher's site

DOI of Published Version

10.1038/sj.onc.1209103

Related Resources

Link to article in PubMed

Journal Title

Oncogene

PubMed ID

16186801