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BMC Cancer. 2016 Jan 25;16:38. doi: 10.1186/s12885-016-2068-9.

LINE-1 silencing by retinoblastoma proteins is effected through the nucleosomal and remodeling deacetylase multiprotein complex.

Author information

1
Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, KY, 40202, USA. diego.montoya-durango@louisville.edu.
2
Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, KY, 40202, USA. kenramos@live.com.
3
Department of Medicine, University of Arizona College of Medicine, Tucson, AZ, 85721, USA. pbojang@email.arizona.edu.
4
Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, KY, 40202, USA. lorellruiz@gmail.com.
5
Department of Health Promotion Sciences, University of Arizona College of Public Health, Tucson, AZ, 85721, USA. inramos@email.arizona.edu.
6
Department of Medicine, University of Arizona College of Medicine, Tucson, AZ, 85721, USA. ksramos@email.arizona.edu.

Abstract

BACKGROUND:

Long Interspersed Nuclear Element-1 (L1) is an oncogenic mammalian retroelement silenced early in development via tightly controlled epigenetic mechanisms. We have previously shown that the regulatory region of human and murine L1s interact with retinoblastoma (RB) proteins to effect retroelement silencing. The present studies were conducted to identify the corepressor complex responsible for RB-mediated silencing of L1.

METHODS:

Chromatin immunoprecipitation and silencing RNA technology were used to identify the repressor complex that silences L1 in human and murine cells.

RESULTS:

Components of the Nucleosomal and Remodeling Deacetylase (NuRD) multiprotein complex specifically enriched the L1 5'-untranslated DNA sequence in human and murine cells. Genetic ablation of RB proteins in murine cells destabilized interactions within the NuRD macromolecular complex and mediated nuclear rearrangement of Mi2-β, an ATP-dependent helicase subunit with nucleosome remodeling activity. Depletion of Mi2-β, RbAP46 and HDAC2 reduced the repressor activity of the NuRD complex and reactivated a synthetic L1 reporter in human cells. Epigenetic reactivation of L1 in RB-null cells by DNA damage was markedly enhanced compared to wild type cells.

CONCLUSIONS:

RB proteins stabilize interactions of the NuRD corepressor complex within the L1 promoter to effect L1 silencing. L1 retroelements may serve as a scaffold on which RB builds heterochromatic regions that regulate chromatin function.

PMID:
26810492
PMCID:
PMC4727354
DOI:
10.1186/s12885-016-2068-9
[Indexed for MEDLINE]
Free PMC Article

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