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


Maximus Peto’s Commentary

This group reports that histone variant macroH2A1.2 is “highly enriched” in ALT telomeres, but they transiently lose this variant. Interestingly, ectopic expression of ATRX can prevent this loss, and the abstract suggest that doing this may be able to prevent ALT by preventing activation of DNA damage response and homologous recombination pathways.


The macroH2A1.2 histone variant links ATRX loss to alternative telomere lengthening.
Nat Struct Mol Biol. 2019 Mar;26(3):213-219.
Kim J, Sun C, Tran AD, Chin PJ, Ruiz PD, Wang K, Gibbons RJ, Gamble MJ, Liu Y, Oberdoerffer P
DOI: 10.1038/s41594-019-0192-3
PubMed publication date (edat): 3/6/2019

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.

PMID: 30833786
Free Full-Text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537592/

Maximus Peto

Max Peto is a longevity researcher and founder of Long Life Labs. A biochemist by training, he studies the biochemistry of aging and longevity and has worked with research organizations such as SENS Research Foundation, Methuselah Foundation, BioAge Labs, Life Extension Foundation, and Ichor Therapeutics. His work at Long Life Labs is focused on empowering people to understand and manage the most critical factors for better health and longer life.

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