Understanding and Targeting the ALT Pathway in Human Breast Cancer
Abstract
Telomeres, the protective elements at the ends of chromosomes, must be maintained for cells to proliferate indefinitely. In many human cancers the telomeric DNA is replenished by the enzyme telomerase. However, a second pathway for telomere maintenance, referred to as the ALT pathway, has increasingly been recognized in human cancers. The genetic basis for activation of ALT is not known, but recent data have identified mutations and loss of ATRX protein as being hallmarks of ALT-immortalized cell lines and tumors. Our efforts to understand the mechanism by which loss of ATRX facilitates telomere recombination have allowed us to exclude telomeric deposition of the histone variant H3.3, changes in subtelomeric methylation, as well as changes in telomeric nucleosomal organization as being relevant mechanisms contributing to this phenotype. I have also determined that ATRX does not function in the known pathways of HDR repression at telomeres. Instead, I find that loss of ATRX produces a telomere-specific defect in chromosome cohesion, thus identifying a potential mechanism through which loss of ATRX could be important for ALT-mediated telomere maintenance.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2013
- Accession Number
- ADA601808
Entities
People
- Courtney A. Lovejoy
- Titia de Lange
Organizations
- The Rockefeller University