The MacroH2A1.2 Histone Variant Links ATRX Loss to Alternative Telomere Lengthening

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2019 Mar 6

PMID 30833786

Citations 29

Authors

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

Affiliations

Soon will be listed here.

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.

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