Predisposition to Cancer Caused by Genetic and Functional Defects of Mammalian Atad5

Predisposition to Cancer Caused by Genetic and Functional Defects of Mammalian Atad5

ATAD5, the human ortholog of yeast Elg1, plays a role in PCNA deubiquitination. Since PCNA modification is important to regulate DNA damage bypass, ATAD5 may be important for suppression of genomic instability in mammals in vivo. To test this hypothesis, we generated heterozygous (Atad5+/m) mice tha...

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Main Authors: Bell, Daphne W., Sikdar, Nilabja, Lee, Kyoo-young, Price, Jessica C., Chatterjee, Raghunath, Park, Hee-Dong, Fox, Jennifer, Ishiai, Masamichi, Rudd, Meghan L., Pollock, Lana M., Fogoros, Sarah K., Mohamed, Hassan, Hanigan, Christin L., Zhang, Suiyuan, Cruz, Pedro, Renaud, Gabriel, Hansen, Nancy F., Cherukuri, Praveen F., Borate, Bhavesh, McManus, Kirk J., Stoepel, Jan, Sipahimalani, Payal, Godwin, Andrew K., Sgroi, Dennis C., Merino, Maria J., Elliot, Gene, Elkahloun, Abdel, Vinson, Charles, Takata, Minoru, Mullikin, James C., Wolfsberg, Tyra G., Hieter, Philip, Lim, Dae-Sik, Myung, Kyungjae
Format: Online
Language:English
Published: Public Library of Science 2011
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3161924/
id pubmed-3161924
recordtype oai_dc
spelling pubmed-31619242011-09-07 Predisposition to Cancer Caused by Genetic and Functional Defects of Mammalian Atad5 Bell, Daphne W. Sikdar, Nilabja Lee, Kyoo-young Price, Jessica C. Chatterjee, Raghunath Park, Hee-Dong Fox, Jennifer Ishiai, Masamichi Rudd, Meghan L. Pollock, Lana M. Fogoros, Sarah K. Mohamed, Hassan Hanigan, Christin L. Zhang, Suiyuan Cruz, Pedro Renaud, Gabriel Hansen, Nancy F. Cherukuri, Praveen F. Borate, Bhavesh McManus, Kirk J. Stoepel, Jan Sipahimalani, Payal Godwin, Andrew K. Sgroi, Dennis C. Merino, Maria J. Elliot, Gene Elkahloun, Abdel Vinson, Charles Takata, Minoru Mullikin, James C. Wolfsberg, Tyra G. Hieter, Philip Lim, Dae-Sik Myung, Kyungjae Research Article ATAD5, the human ortholog of yeast Elg1, plays a role in PCNA deubiquitination. Since PCNA modification is important to regulate DNA damage bypass, ATAD5 may be important for suppression of genomic instability in mammals in vivo. To test this hypothesis, we generated heterozygous (Atad5+/m) mice that were haploinsuffficient for Atad5. Atad5+/m mice displayed high levels of genomic instability in vivo, and Atad5+/m mouse embryonic fibroblasts (MEFs) exhibited molecular defects in PCNA deubiquitination in response to DNA damage, as well as DNA damage hypersensitivity and high levels of genomic instability, apoptosis, and aneuploidy. Importantly, 90% of haploinsufficient Atad5+/m mice developed tumors, including sarcomas, carcinomas, and adenocarcinomas, between 11 and 20 months of age. High levels of genomic alterations were evident in tumors that arose in the Atad5+/m mice. Consistent with a role for Atad5 in suppressing tumorigenesis, we also identified somatic mutations of ATAD5 in 4.6% of sporadic human endometrial tumors, including two nonsense mutations that resulted in loss of proper ATAD5 function. Taken together, our findings indicate that loss-of-function mutations in mammalian Atad5 are sufficient to cause genomic instability and tumorigenesis. Public Library of Science 2011-08-25 /pmc/articles/PMC3161924/ /pubmed/21901109 http://dx.doi.org/10.1371/journal.pgen.1002245 Text en This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Bell, Daphne W.
Sikdar, Nilabja
Lee, Kyoo-young
Price, Jessica C.
Chatterjee, Raghunath
Park, Hee-Dong
Fox, Jennifer
Ishiai, Masamichi
Rudd, Meghan L.
Pollock, Lana M.
Fogoros, Sarah K.
Mohamed, Hassan
Hanigan, Christin L.
Zhang, Suiyuan
Cruz, Pedro
Renaud, Gabriel
Hansen, Nancy F.
Cherukuri, Praveen F.
Borate, Bhavesh
McManus, Kirk J.
Stoepel, Jan
Sipahimalani, Payal
Godwin, Andrew K.
Sgroi, Dennis C.
Merino, Maria J.
Elliot, Gene
Elkahloun, Abdel
Vinson, Charles
Takata, Minoru
Mullikin, James C.
Wolfsberg, Tyra G.
Hieter, Philip
Lim, Dae-Sik
Myung, Kyungjae
spellingShingle Bell, Daphne W.
Sikdar, Nilabja
Lee, Kyoo-young
Price, Jessica C.
Chatterjee, Raghunath
Park, Hee-Dong
Fox, Jennifer
Ishiai, Masamichi
Rudd, Meghan L.
Pollock, Lana M.
Fogoros, Sarah K.
Mohamed, Hassan
Hanigan, Christin L.
Zhang, Suiyuan
Cruz, Pedro
Renaud, Gabriel
Hansen, Nancy F.
Cherukuri, Praveen F.
Borate, Bhavesh
McManus, Kirk J.
Stoepel, Jan
Sipahimalani, Payal
Godwin, Andrew K.
Sgroi, Dennis C.
Merino, Maria J.
Elliot, Gene
Elkahloun, Abdel
Vinson, Charles
Takata, Minoru
Mullikin, James C.
Wolfsberg, Tyra G.
Hieter, Philip
Lim, Dae-Sik
Myung, Kyungjae
Predisposition to Cancer Caused by Genetic and Functional Defects of Mammalian Atad5
author_facet Bell, Daphne W.
Sikdar, Nilabja
Lee, Kyoo-young
Price, Jessica C.
Chatterjee, Raghunath
Park, Hee-Dong
Fox, Jennifer
Ishiai, Masamichi
Rudd, Meghan L.
Pollock, Lana M.
Fogoros, Sarah K.
Mohamed, Hassan
Hanigan, Christin L.
Zhang, Suiyuan
Cruz, Pedro
Renaud, Gabriel
Hansen, Nancy F.
Cherukuri, Praveen F.
Borate, Bhavesh
McManus, Kirk J.
Stoepel, Jan
Sipahimalani, Payal
Godwin, Andrew K.
Sgroi, Dennis C.
Merino, Maria J.
Elliot, Gene
Elkahloun, Abdel
Vinson, Charles
Takata, Minoru
Mullikin, James C.
Wolfsberg, Tyra G.
Hieter, Philip
Lim, Dae-Sik
Myung, Kyungjae
author_sort Bell, Daphne W.
title Predisposition to Cancer Caused by Genetic and Functional Defects of Mammalian Atad5
title_short Predisposition to Cancer Caused by Genetic and Functional Defects of Mammalian Atad5
title_full Predisposition to Cancer Caused by Genetic and Functional Defects of Mammalian Atad5
title_fullStr Predisposition to Cancer Caused by Genetic and Functional Defects of Mammalian Atad5
title_full_unstemmed Predisposition to Cancer Caused by Genetic and Functional Defects of Mammalian Atad5
title_sort predisposition to cancer caused by genetic and functional defects of mammalian atad5
description ATAD5, the human ortholog of yeast Elg1, plays a role in PCNA deubiquitination. Since PCNA modification is important to regulate DNA damage bypass, ATAD5 may be important for suppression of genomic instability in mammals in vivo. To test this hypothesis, we generated heterozygous (Atad5+/m) mice that were haploinsuffficient for Atad5. Atad5+/m mice displayed high levels of genomic instability in vivo, and Atad5+/m mouse embryonic fibroblasts (MEFs) exhibited molecular defects in PCNA deubiquitination in response to DNA damage, as well as DNA damage hypersensitivity and high levels of genomic instability, apoptosis, and aneuploidy. Importantly, 90% of haploinsufficient Atad5+/m mice developed tumors, including sarcomas, carcinomas, and adenocarcinomas, between 11 and 20 months of age. High levels of genomic alterations were evident in tumors that arose in the Atad5+/m mice. Consistent with a role for Atad5 in suppressing tumorigenesis, we also identified somatic mutations of ATAD5 in 4.6% of sporadic human endometrial tumors, including two nonsense mutations that resulted in loss of proper ATAD5 function. Taken together, our findings indicate that loss-of-function mutations in mammalian Atad5 are sufficient to cause genomic instability and tumorigenesis.
publisher Public Library of Science
publishDate 2011
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3161924/
_version_ 1611472516204724224

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