Alternative Lengthening of Telomeres: Building Bridges To Connect Chromosome Ends

Song My Hoang; Roderick J O'Sullivan

doi:10.1016/j.trecan.2019.12.009

Alternative Lengthening of Telomeres: Building Bridges To Connect Chromosome Ends

Trends Cancer. 2020 Mar;6(3):247-260. doi: 10.1016/j.trecan.2019.12.009. Epub 2020 Jan 23.

Authors

Song My Hoang¹, Roderick J O'Sullivan²

Affiliations

¹ Department of Pharmacology and Chemical Biology, Hillman Cancer Center, University of Pittsburgh School of Medicine (UPMC), Pittsburgh, PA, USA.
² Department of Pharmacology and Chemical Biology, Hillman Cancer Center, University of Pittsburgh School of Medicine (UPMC), Pittsburgh, PA, USA. Electronic address: osullivanr@upmc.edu.

Abstract

Alternative lengthening of telomeres (ALT) is a mechanism of telomere maintenance that is observed in many of the most recalcitrant cancer subtypes. Telomeres in ALT cancer cells exhibit a distinctive nucleoprotein architecture shaped by the mismanagement of chromatin that fosters cycles of DNA damage and replicative stress that activate homology-directed repair (HDR). Mutations in specific chromatin-remodeling factors appear to be key determinants of the emergence and survival of ALT cancer cells. However, these may represent vulnerabilities for the targeted elimination of ALT cancer cells that infiltrate tissues and organs to become devastating tumors. In this review we examine recent findings that provide new insights into the factors and mechanisms that mediate telomere length maintenance and survival of ALT cancer cells.

Keywords: DNA damage; cancer; homology-directed repair; replicative stress; telomere.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

MeSH terms

Chromatin / ultrastructure
Clonal Evolution
Co-Repressor Proteins / antagonists & inhibitors
Co-Repressor Proteins / physiology
DNA Damage
DNA Repair
DNA Replication
DNA, Neoplasm / metabolism
DNA, Neoplasm / ultrastructure
Histones / physiology
Homologous Recombination
Humans
Models, Genetic
Molecular Chaperones / antagonists & inhibitors
Molecular Chaperones / physiology
Mutation
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / genetics
Neoplasm Proteins / physiology
Neoplasms / genetics*
Neoplasms / ultrastructure
Nucleic Acid Conformation
Telomerase / genetics
Telomerase / physiology
Telomere Homeostasis*
X-linked Nuclear Protein / antagonists & inhibitors
X-linked Nuclear Protein / physiology

Substances

Chromatin
Co-Repressor Proteins
DAXX protein, human
DNA, Neoplasm
Histones
Molecular Chaperones
Neoplasm Proteins
Telomerase
ATRX protein, human
X-linked Nuclear Protein

Grants and funding

R01 CA207209/CA/NCI NIH HHS/United States