The macroH2A1.2 histone variant links ATRX loss to alternative telomere lengthening

Jeongkyu Kim, Chongkui Sun, Andy D. Tran, Pei Ju Chin, Penelope D. Ruiz, Kun Wang, Richard J. Gibbons, Matthew J. Gamble, Yie Liu, Philipp Oberdoerffer

Research output: Contribution to journalArticle

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Abstract

The growth of telomerase-deficient cancers depends on the alternative lengthening of telomeres (ALT), a homology-directed telomere-maintenance pathway. ALT telomeres exhibit a unique chromatin environment and generally lack the nucleosome remodeler ATRX, pointing to an epigenetic basis for ALT. Recently, we identified a protective role for the ATRX-interacting macroH2A1.2 histone variant during homologous recombination and replication stress (RS). Consistent with an inherent susceptibility to RS, we show that human ALT telomeres are highly enriched for macroH2A1.2. However, in contrast to ATRX-proficient cells, ALT telomeres transiently lose macroH2A1.2 during acute RS to facilitate DNA double-strand break (DSB) formation, a process that is almost completely prevented by ectopic ATRX expression. Telomeric macroH2A1.2 is re-deposited in a DNA damage response (DDR)-dependent manner to promote homologous recombination-associated ALT pathways. Our findings thus identify the dynamic exchange of macroH2A1.2 on chromatin as an epigenetic link among ATRX loss, RS-induced DDR initiation and telomere maintenance via homologous recombination.

Original languageEnglish (US)
Pages (from-to)213-219
Number of pages7
JournalNature Structural and Molecular Biology
Volume26
Issue number3
DOIs
StatePublished - Mar 1 2019

Fingerprint

Telomere Homeostasis
Histones
Telomere
Homologous Recombination
Epigenomics
DNA Damage
Chromatin
Maintenance
Double-Stranded DNA Breaks
Nucleosomes
Telomerase
macroH2A histone
Growth

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Kim, J., Sun, C., Tran, A. D., Chin, P. J., Ruiz, P. D., Wang, K., ... Oberdoerffer, P. (2019). The macroH2A1.2 histone variant links ATRX loss to alternative telomere lengthening. Nature Structural and Molecular Biology, 26(3), 213-219. https://doi.org/10.1038/s41594-019-0192-3

The macroH2A1.2 histone variant links ATRX loss to alternative telomere lengthening. / Kim, Jeongkyu; Sun, Chongkui; Tran, Andy D.; Chin, Pei Ju; Ruiz, Penelope D.; Wang, Kun; Gibbons, Richard J.; Gamble, Matthew J.; Liu, Yie; Oberdoerffer, Philipp.

In: Nature Structural and Molecular Biology, Vol. 26, No. 3, 01.03.2019, p. 213-219.

Research output: Contribution to journalArticle

Kim, J, Sun, C, Tran, AD, Chin, PJ, Ruiz, PD, Wang, K, Gibbons, RJ, Gamble, MJ, Liu, Y & Oberdoerffer, P 2019, 'The macroH2A1.2 histone variant links ATRX loss to alternative telomere lengthening', Nature Structural and Molecular Biology, vol. 26, no. 3, pp. 213-219. https://doi.org/10.1038/s41594-019-0192-3
Kim, Jeongkyu ; Sun, Chongkui ; Tran, Andy D. ; Chin, Pei Ju ; Ruiz, Penelope D. ; Wang, Kun ; Gibbons, Richard J. ; Gamble, Matthew J. ; Liu, Yie ; Oberdoerffer, Philipp. / The macroH2A1.2 histone variant links ATRX loss to alternative telomere lengthening. In: Nature Structural and Molecular Biology. 2019 ; Vol. 26, No. 3. pp. 213-219.
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