Prosurvival long noncoding RNA PINCR regulates a subset of p53 targets in human colorectal cancer cells by binding to Matrin 3

Ritu Chaudhary; Berkley Gryder; Wendy S. Woods; Murugan Subramanian; Matthew F. Jones; Xiao Ling Li; Lisa M. Jenkins; Svetlana A. Shabalina; Min Mo; Mary Dasso; Yuan Yang; Lalage M. Wakefield; Yuelin Zhu; Susan M. Frier; Branden S. Moriarity; Kannanganattu V. Prasanth; Pablo Perez-Pinera; Ashish Lal

doi:10.7554/eLife.23244

Prosurvival long noncoding RNA PINCR regulates a subset of p53 targets in human colorectal cancer cells by binding to Matrin 3

Ritu Chaudhary, Berkley Gryder, Wendy S. Woods, Murugan Subramanian, Matthew F. Jones, Xiao Ling Li, Lisa M. Jenkins, Svetlana A. Shabalina, Min Mo, Mary Dasso, Yuan Yang, Lalage M. Wakefield, Yuelin Zhu, Susan M. Frier, Branden S. Moriarity, Kannanganattu V. Prasanth, Pablo Perez-Pinera, Ashish Lal

Pediatric Hematology/Oncology

Research output: Contribution to journal › Article › peer-review

57 Scopus citations

Abstract

Thousands of long noncoding RNAs (lncRNAs) have been discovered, yet the function of the vast majority remains unclear. Here, we show that a p53-regulated lncRNA which we named PINCR (p53-induced noncoding RNA), is induced ~100-fold after DNA damage and exerts a prosurvival function in human colorectal cancer cells (CRC) in vitro and tumor growth in vivo. Targeted deletion of PINCR in CRC cells significantly impaired G1 arrest and induced hypersensitivity to chemotherapeutic drugs. PINCR regulates the induction of a subset of p53 targets involved in G1 arrest and apoptosis, including BTG2, RRM2B and GPX1. Using a novel RNA pulldown approach that utilized endogenous S1-tagged PINCR, we show that PINCR associates with the enhancer region of these genes by binding to RNA-binding protein Matrin 3 that, in turn, associates with p53. Our findings uncover a critical prosurvival function of a p53/PINCR/Matrin 3 axis in response to DNA damage in CRC cells.

Original language	English (US)
Article number	e23244
Journal	eLife
Volume	6
DOIs	https://doi.org/10.7554/eLife.23244
State	Published - Jun 5 2017

Bibliographical note

Funding Information:
We thank Tom Misteli, Glenn Merlino, Susan Gottesman, Shiv Grewal, Curtis Harris and Javed Khan for their critical comments on the manuscript and Bert Vogelstein for the isogenic cell lines. This research was supported by the Intramural Research Program (AL, LW, LMJ) of the National Cancer Institute (NCI), Center for Cancer Research (CCR), NIH. KVP lab is supported by grants from NIH [GM088252] and American Cancer Society [RSG-11-174-01-RMC]. National Cancer InstituteNIH IRP Ashish Lal.

Publisher Copyright:
© 2017, eLife Sciences Publications Ltd. All rights reserved.

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10.7554/eLife.23244

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470874

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Chaudhary, R., Gryder, B., Woods, W. S., Subramanian, M., Jones, M. F., Li, X. L., Jenkins, L. M., Shabalina, S. A., Mo, M., Dasso, M., Yang, Y., Wakefield, L. M., Zhu, Y., Frier, S. M., Moriarity, B. S., Prasanth, K. V., Perez-Pinera, P., & Lal, A. (2017). Prosurvival long noncoding RNA PINCR regulates a subset of p53 targets in human colorectal cancer cells by binding to Matrin 3. eLife, 6, [e23244]. https://doi.org/10.7554/eLife.23244

Chaudhary, R, Gryder, B, Woods, WS, Subramanian, M, Jones, MF, Li, XL, Jenkins, LM, Shabalina, SA, Mo, M, Dasso, M, Yang, Y, Wakefield, LM, Zhu, Y, Frier, SM, Moriarity, BS, Prasanth, KV, Perez-Pinera, P & Lal, A 2017, 'Prosurvival long noncoding RNA PINCR regulates a subset of p53 targets in human colorectal cancer cells by binding to Matrin 3', eLife, vol. 6, e23244. https://doi.org/10.7554/eLife.23244

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title = "Prosurvival long noncoding RNA PINCR regulates a subset of p53 targets in human colorectal cancer cells by binding to Matrin 3",

abstract = "Thousands of long noncoding RNAs (lncRNAs) have been discovered, yet the function of the vast majority remains unclear. Here, we show that a p53-regulated lncRNA which we named PINCR (p53-induced noncoding RNA), is induced ~100-fold after DNA damage and exerts a prosurvival function in human colorectal cancer cells (CRC) in vitro and tumor growth in vivo. Targeted deletion of PINCR in CRC cells significantly impaired G1 arrest and induced hypersensitivity to chemotherapeutic drugs. PINCR regulates the induction of a subset of p53 targets involved in G1 arrest and apoptosis, including BTG2, RRM2B and GPX1. Using a novel RNA pulldown approach that utilized endogenous S1-tagged PINCR, we show that PINCR associates with the enhancer region of these genes by binding to RNA-binding protein Matrin 3 that, in turn, associates with p53. Our findings uncover a critical prosurvival function of a p53/PINCR/Matrin 3 axis in response to DNA damage in CRC cells.",

author = "Ritu Chaudhary and Berkley Gryder and Woods, {Wendy S.} and Murugan Subramanian and Jones, {Matthew F.} and Li, {Xiao Ling} and Jenkins, {Lisa M.} and Shabalina, {Svetlana A.} and Min Mo and Mary Dasso and Yuan Yang and Wakefield, {Lalage M.} and Yuelin Zhu and Frier, {Susan M.} and Moriarity, {Branden S.} and Prasanth, {Kannanganattu V.} and Pablo Perez-Pinera and Ashish Lal",

note = "Funding Information: We thank Tom Misteli, Glenn Merlino, Susan Gottesman, Shiv Grewal, Curtis Harris and Javed Khan for their critical comments on the manuscript and Bert Vogelstein for the isogenic cell lines. This research was supported by the Intramural Research Program (AL, LW, LMJ) of the National Cancer Institute (NCI), Center for Cancer Research (CCR), NIH. KVP lab is supported by grants from NIH [GM088252] and American Cancer Society [RSG-11-174-01-RMC]. National Cancer InstituteNIH IRP Ashish Lal. Publisher Copyright: {\textcopyright} 2017, eLife Sciences Publications Ltd. All rights reserved.",

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AU - Chaudhary, Ritu

AU - Gryder, Berkley

AU - Woods, Wendy S.

AU - Subramanian, Murugan

AU - Jones, Matthew F.

AU - Li, Xiao Ling

AU - Jenkins, Lisa M.

AU - Shabalina, Svetlana A.

AU - Mo, Min

AU - Dasso, Mary

AU - Yang, Yuan

AU - Wakefield, Lalage M.

AU - Zhu, Yuelin

AU - Frier, Susan M.

AU - Moriarity, Branden S.

AU - Prasanth, Kannanganattu V.

AU - Perez-Pinera, Pablo

AU - Lal, Ashish

N1 - Funding Information: We thank Tom Misteli, Glenn Merlino, Susan Gottesman, Shiv Grewal, Curtis Harris and Javed Khan for their critical comments on the manuscript and Bert Vogelstein for the isogenic cell lines. This research was supported by the Intramural Research Program (AL, LW, LMJ) of the National Cancer Institute (NCI), Center for Cancer Research (CCR), NIH. KVP lab is supported by grants from NIH [GM088252] and American Cancer Society [RSG-11-174-01-RMC]. National Cancer InstituteNIH IRP Ashish Lal. Publisher Copyright: © 2017, eLife Sciences Publications Ltd. All rights reserved.

PY - 2017/6/5

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N2 - Thousands of long noncoding RNAs (lncRNAs) have been discovered, yet the function of the vast majority remains unclear. Here, we show that a p53-regulated lncRNA which we named PINCR (p53-induced noncoding RNA), is induced ~100-fold after DNA damage and exerts a prosurvival function in human colorectal cancer cells (CRC) in vitro and tumor growth in vivo. Targeted deletion of PINCR in CRC cells significantly impaired G1 arrest and induced hypersensitivity to chemotherapeutic drugs. PINCR regulates the induction of a subset of p53 targets involved in G1 arrest and apoptosis, including BTG2, RRM2B and GPX1. Using a novel RNA pulldown approach that utilized endogenous S1-tagged PINCR, we show that PINCR associates with the enhancer region of these genes by binding to RNA-binding protein Matrin 3 that, in turn, associates with p53. Our findings uncover a critical prosurvival function of a p53/PINCR/Matrin 3 axis in response to DNA damage in CRC cells.

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Prosurvival long noncoding RNA PINCR regulates a subset of p53 targets in human colorectal cancer cells by binding to Matrin 3

Abstract

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