PCAT-1, a long noncoding RNA, regulates BRCA2 and controls homologous recombination in cancer

John R. Prensner; Wei Chen; Matthew K. Iyer; Qi Cao; Teng Ma; Sumin Han; Anirban Sahu; Rohit Malik; Kari Wilder-Romans; Nora Navone; Christopher J. Logothetis; John C. Araujo; Louis L. Pisters; Ashutosh K. Tewari; Christine E. Canman; Karen E. Knudsen; Naoki Kitabayashi; Mark A. Rubin; Francesca Demichelis; Theodore S. Lawrence; Arul M. Chinnaiyan; Felix Y. Feng

doi:10.1158/0008-5472.CAN-13-3159

PCAT-1, a long noncoding RNA, regulates BRCA2 and controls homologous recombination in cancer

John R. Prensner, Wei Chen, Matthew K. Iyer, Qi Cao, Teng Ma, Sumin Han, Anirban Sahu, Rohit Malik, Kari Wilder-Romans, Nora Navone, Christopher J. Logothetis, John C. Araujo, Louis L. Pisters, Ashutosh K. Tewari, Christine E. Canman, Karen E. Knudsen, Naoki Kitabayashi, Mark A. Rubin, Francesca Demichelis, Theodore S. LawrenceArul M. Chinnaiyan, Felix Y. Feng

Houston Methodist

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

229 Scopus citations

Abstract

Impairment of double-stranded DNA break (DSB) repair is essential to many cancers. However, although mutations in DSB repair proteins are common in hereditary cancers, mechanisms of impaired DSB repair in sporadic cancers remain incompletely understood. Here, we describe the first role for a long noncoding RNA (lncRNA) in DSB repair in prostate cancer. We identify PCAT-1, a prostate cancer outlier lncRNA, which regulates cell response to genotoxic stress. PCAT-1 expression produces a functional deficiency in homologous recombination through its repression of the BRCA2 tumor suppressor, which, in turn, imparts a high sensitivity to smallmolecule inhibitors of PARP1. These effects reflected a posttranscriptional repression of the BRCA2 30UTR by PCAT-1. Our observations thus offer a novel mechanism of "BRCAness" in sporadic cancers.

Original language	English (US)
Pages (from-to)	1651-1660
Number of pages	10
Journal	Cancer research
Volume	74
Issue number	6
DOIs	https://doi.org/10.1158/0008-5472.CAN-13-3159
State	Published - Mar 15 2014

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1158/0008-5472.CAN-13-3159

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Prensner, J. R., Chen, W., Iyer, M. K., Cao, Q., Ma, T., Han, S., Sahu, A., Malik, R., Wilder-Romans, K., Navone, N., Logothetis, C. J., Araujo, J. C., Pisters, L. L., Tewari, A. K., Canman, C. E., Knudsen, K. E., Kitabayashi, N., Rubin, M. A., Demichelis, F., ... Feng, F. Y. (2014). PCAT-1, a long noncoding RNA, regulates BRCA2 and controls homologous recombination in cancer. Cancer research, 74(6), 1651-1660. https://doi.org/10.1158/0008-5472.CAN-13-3159

Prensner, JR, Chen, W, Iyer, MK, Cao, Q, Ma, T, Han, S, Sahu, A, Malik, R, Wilder-Romans, K, Navone, N, Logothetis, CJ, Araujo, JC, Pisters, LL, Tewari, AK, Canman, CE, Knudsen, KE, Kitabayashi, N, Rubin, MA, Demichelis, F, Lawrence, TS, Chinnaiyan, AM & Feng, FY 2014, 'PCAT-1, a long noncoding RNA, regulates BRCA2 and controls homologous recombination in cancer', Cancer research, vol. 74, no. 6, pp. 1651-1660. https://doi.org/10.1158/0008-5472.CAN-13-3159

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abstract = "Impairment of double-stranded DNA break (DSB) repair is essential to many cancers. However, although mutations in DSB repair proteins are common in hereditary cancers, mechanisms of impaired DSB repair in sporadic cancers remain incompletely understood. Here, we describe the first role for a long noncoding RNA (lncRNA) in DSB repair in prostate cancer. We identify PCAT-1, a prostate cancer outlier lncRNA, which regulates cell response to genotoxic stress. PCAT-1 expression produces a functional deficiency in homologous recombination through its repression of the BRCA2 tumor suppressor, which, in turn, imparts a high sensitivity to smallmolecule inhibitors of PARP1. These effects reflected a posttranscriptional repression of the BRCA2 30UTR by PCAT-1. Our observations thus offer a novel mechanism of {"}BRCAness{"} in sporadic cancers.",

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AU - Han, Sumin

AU - Sahu, Anirban

AU - Malik, Rohit

AU - Wilder-Romans, Kari

AU - Navone, Nora

AU - Logothetis, Christopher J.

AU - Araujo, John C.

AU - Pisters, Louis L.

AU - Tewari, Ashutosh K.

AU - Canman, Christine E.

AU - Knudsen, Karen E.

AU - Kitabayashi, Naoki

AU - Rubin, Mark A.

AU - Demichelis, Francesca

AU - Lawrence, Theodore S.

AU - Chinnaiyan, Arul M.

AU - Feng, Felix Y.

PY - 2014/3/15

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AB - Impairment of double-stranded DNA break (DSB) repair is essential to many cancers. However, although mutations in DSB repair proteins are common in hereditary cancers, mechanisms of impaired DSB repair in sporadic cancers remain incompletely understood. Here, we describe the first role for a long noncoding RNA (lncRNA) in DSB repair in prostate cancer. We identify PCAT-1, a prostate cancer outlier lncRNA, which regulates cell response to genotoxic stress. PCAT-1 expression produces a functional deficiency in homologous recombination through its repression of the BRCA2 tumor suppressor, which, in turn, imparts a high sensitivity to smallmolecule inhibitors of PARP1. These effects reflected a posttranscriptional repression of the BRCA2 30UTR by PCAT-1. Our observations thus offer a novel mechanism of "BRCAness" in sporadic cancers.

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PCAT-1, a long noncoding RNA, regulates BRCA2 and controls homologous recombination in cancer

Abstract

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