The unlimited replicative capacity of human tumor cells relies on their ability to counteract the progressive loss of telomeric DNA that accompanies cell division. Eighty- five percent of cancers achieve this by up-regulating telomerase, the enzyme that adds telomere repeats to chromosome ends. The remaining 15% activate ALT (alternative lengthening of telomeres), a recombination-based mechanism. The observation that ALT is activated in a significant fraction of human tumors, combined with the notion that it may provide an adaptive mechanism to anti-telomerase therapies, indicate it as an important target for anti-cancer strategies. Recent studies identified the chromatin- remodeling factor ATRX as the protein most frequently lost in ALT, but how this loss impacts telomere recombination is not known. Our studies reveal a mechanism: loss of ATRX suppresses resolution of sister telomere cohesion at mitosis. The resulting persistent telomere cohesion promotes chromatid exchange between sister telomeres, while it suppresses inappropriate recombination between non-sisters. We hypothesize that persistent telomere cohesion is a critical component of the ALT cell state.
In Aim 1 we will elucidate the mechanisms by which loss of ATRX promotes ALT cell recombination and growth.
In Aim 2 we will investigate how loss of ATRX leads to activation of ALT.
In Aim 3 we will explore the hypothesis that up-regulation of the cohesin subunit SA1 in tumors promotes persistent telomere cohesion and an ALT-like mechanism of telomere maintenance. Understanding how recombination mediates telomere length maintenance in ALT cancers will provide insights into basic mechanisms of recombination as well as provide targets for anti-cancer therapies.

Public Health Relevance

The unlimited replicative capacity of human tumor cells requires a telomere maintenance mechanism. Eighty-five percent of cancers achieve this by activating telomerase, while the remaining 15% activate ALT (alternative lengthening of telomeres), a recombination- based mechanism. Understanding how recombination mediates telomere length maintenance in ALT cancers will provide insights into basic mechanisms of recombination as well as provide targets for anti-cancer therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA200751-02
Application #
9294009
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Witkin, Keren L
Project Start
2016-07-01
Project End
2021-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016