BRM-SWI/SNF chromatin remodeling complex enables functional telomeres by promoting co-expression of TRF2 and TRF1

PLoS Genet. 2020 Jun 5;16(6):e1008799. doi: 10.1371/journal.pgen.1008799. eCollection 2020 Jun.

Abstract

TRF2 and TRF1 are a key component in shelterin complex that associates with telomeric DNA and protects chromosome ends. BRM is a core ATPase subunit of SWI/SNF chromatin remodeling complex. Whether and how BRM-SWI/SNF complex is engaged in chromatin end protection by telomeres is unknown. Here, we report that depletion of BRM does not affect heterochromatin state of telomeres, but results in telomere dysfunctional phenomena including telomere uncapping and replication defect. Mechanistically, expression of TRF2 and TRF1 is jointly regulated by BRM-SWI/SNF complex, which is localized to promoter region of both genes and facilitates their transcription. BRM-deficient cells bear increased TRF2-free or TRF1-free telomeres due to insufficient expression. Importantly, BRM depletion-induced telomere uncapping or replication defect can be rescued by compensatory expression of exogenous TRF2 or TRF1, respectively. Together, these results identify a new function of BRM-SWI/SNF complex in enabling functional telomeres for maintaining genome stability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosomal Proteins, Non-Histone / metabolism*
  • Genomic Instability
  • HEK293 Cells
  • HeLa Cells
  • Hep G2 Cells
  • Heterochromatin / metabolism
  • Humans
  • Promoter Regions, Genetic
  • Telomere / metabolism*
  • Telomeric Repeat Binding Protein 1 / genetics*
  • Telomeric Repeat Binding Protein 1 / metabolism
  • Telomeric Repeat Binding Protein 2 / genetics*
  • Telomeric Repeat Binding Protein 2 / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Chromosomal Proteins, Non-Histone
  • Heterochromatin
  • SMARCA2 protein, human
  • SWI-SNF-B chromatin-remodeling complex
  • TERF2 protein, human
  • Telomeric Repeat Binding Protein 1
  • Telomeric Repeat Binding Protein 2
  • Transcription Factors

Grant support

This work was supported by the National Natural Science Foundation of China Grants (31970683, 31701196, 81702756), the National Key R&D Program of China (2018YFA0107000), and Guangzhou Municipal People's Livelihood Science and Technology Plan (201803010108 and 201604016111), Guangdong Basic and Applied Basic Research Foundation (2020A1515011522) and the Fundamental Research Funds for the Central Universities (18lgpy52). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.