TY - JOUR
T1 - ATRX loss induces multiple hallmarks of the alternative lengthening of telomeres (ALT) phenotype in human glioma cell lines in a cell line-specific manner
AU - Brosnan-Cashman, Jacqueline A.
AU - Yuan, Ming
AU - Graham, Mindy K.
AU - Rizzo, Anthony J.
AU - Myers, Kaylar M.
AU - Davis, Christine
AU - Zhang, Rebecca
AU - Esopi, David M.
AU - Raabe, Eric H.
AU - Eberhart, Charles G.
AU - Heaphy, Christopher M.
AU - Meeker, Alan K.
N1 - Funding Information:
J.B.C was supported by a National Cancer Institute (https://www.cancer.gov) training grant (2T32CA009110-39A1) and a postdoctoral fellowship from the Rally Foundation for Childhood Cancer Research (https://rallyfoundation.org), The Truth 365 (https://www.thetruth365.org), and Open Hands Overflowing Hearts (http:// openhandsoverflowinghearts.org). M.K.G was supported by a National Cancer Institute (https:// www.cancer.gov) training grant (F32CA213742). A. K.M was supported by National Cancer Institute (https://www.cancer.gov) grant 5R01CA172380-05. Core facilities were funded through a National Cancer Institute (https://www.cancer.gov) Cancer Center Support grant (P30 CA006973). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Funding Information:
Funding: J.B.C was supported by a National Cancer Institute (https://www.cancer.gov) training grant (2T32CA009 10-39A1) and a postdoctoral fellowship from the Rally Foundation for Childhood Cancer Research (https://rallyfoundation.org), The Truth 365 (https://www.thetruth365.org), and Open Hands Overflowing Hearts (http://openhandsoverflowinghearts.org). M.K.G was supported by a National Cancer Institute (https://www.cancer.gov) training grant (F32CA213742). A.K.M was supported by National Cancer Institute (https://www.cancer.gov) grant 5R01CA172380-05. Core facilities were funded through a National Cancer Institute (https://www.cancer.gov) Cancer Center Support grant (P30 CA006973). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2018 Brosnan-Cashman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2018/9
Y1 - 2018/9
N2 - Cancers must maintain their telomeres at lengths sufficient for cell survival. In several cancer subtypes, a recombination-like mechanism termed alternative lengthening of telomeres (ALT), is frequently used for telomere length maintenance. Cancers utilizing ALT often have lost functional ATRX, a chromatin remodeling protein, through mutation or deletion, thereby strongly implicating ATRX as an ALT suppressor. Herein, we have generated functional ATRX knockouts in four telomerase-positive, ALT-negative human glioma cell lines: MOG-G-UVW, SF188, U-251 and UW479. After loss of ATRX, two of the four cell lines (U-251 and UW479) show multiple characteristics of ALT-positive cells, including ultrabright telomeric DNA foci, ALT-associated PML bodies, and c-circles. However, telomerase activity and overall telomere length heterogeneity are unaffected after ATRX loss, regardless of cellular context. The two cell lines that showed ALT hallmarks after complete ATRX loss also did so upon ATRX depletion via shRNA-mediated knockdown. These results suggest that other genomic or epigenetic events, in addition to ATRX loss, are necessary for the induction of ALT in human cancer.
AB - Cancers must maintain their telomeres at lengths sufficient for cell survival. In several cancer subtypes, a recombination-like mechanism termed alternative lengthening of telomeres (ALT), is frequently used for telomere length maintenance. Cancers utilizing ALT often have lost functional ATRX, a chromatin remodeling protein, through mutation or deletion, thereby strongly implicating ATRX as an ALT suppressor. Herein, we have generated functional ATRX knockouts in four telomerase-positive, ALT-negative human glioma cell lines: MOG-G-UVW, SF188, U-251 and UW479. After loss of ATRX, two of the four cell lines (U-251 and UW479) show multiple characteristics of ALT-positive cells, including ultrabright telomeric DNA foci, ALT-associated PML bodies, and c-circles. However, telomerase activity and overall telomere length heterogeneity are unaffected after ATRX loss, regardless of cellular context. The two cell lines that showed ALT hallmarks after complete ATRX loss also did so upon ATRX depletion via shRNA-mediated knockdown. These results suggest that other genomic or epigenetic events, in addition to ATRX loss, are necessary for the induction of ALT in human cancer.
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U2 - 10.1371/journal.pone.0204159
DO - 10.1371/journal.pone.0204159
M3 - Article
C2 - 30226859
AN - SCOPUS:85053627086
SN - 1932-6203
VL - 13
JO - PloS one
JF - PloS one
IS - 9
M1 - e0204159
ER -