While many prefer matters to be straightforward, some prefer to think “outside the box” and conjure up an alternative to the norm. Cancer cells are much the same; while most remain on the straight and narrow and employ the telomerase holoenzyme complex to maintain their telomeres, a significant fraction go their own way and use alternative lengthening of telomeres (ALT).
ALT relies on homology-directed telomere maintenance and creative studies have uncovered an epigenetic part to the ALT story: ALT cells lack the ATRX chromatin remodeler, and loss of the histone chaperone ASF1 induces ALT in telomerase-positive cells. One hypothesis states that perturbations to the unique chromatin environment of ALT telomeres increases replication stress susceptibility, promotes DNA double-strand break formation, and thereby triggers homologous recombination-dependent telomere lengthening. In the hope of straightening out the coordination of these processes, canny researchers led by Yie Liu (National Institute on Aging) and Philipp Oberdoerffer (National Institutes of Health, Bethesda, USA) recently dared to think different and sought a link between ATRX loss, the ALT phenotype, and macroH2A1.2, an ATRX-interacting alternatively-spliced histone variant with protective roles during homologous recombination and replication stress.
Here are the details from this alternative epigenetic look at ALT from Kim and colleagues:
- Chromatin immunoprecipitation-based studies demonstrated that telomerase-positive and ALT human cancer cells display telomeric and subtelomeric enrichment of macroH2A1.2, with the highest levels observed in ALT cells
- Downregulation of macroH2A1.2 via shRNA and RNAi levels prompts loss of the ALT phenotype and induces a BRCA1 DNA damage factor-associated response
- Telomerase-positive cells retain telomeric macroH2A1.2 at stalled replication forks during replication stress thanks to ATRX activity, which protects from excessive DNA damage in ALT-negative cells
- However, telomeres in ALT cells lose macroH2A1.2 during replication stress, thereby facilitating DNA double-strand break formation
- The subsequent BRCA1-led DNA damage response redeposits macroH2A1.2 at DNA double-strand breaks at telomeres in ALT cells to allow homologous recombination-mediated telomere extension
- ATRX overexpression in ALT cells inhibits macroH2A1.2 loss
Overall, these findings suggest that the macroH2A1.2 alternatively-spliced histone variant represents a modulator of both telomere-associated DNA damage formation, subsequent homology-directed repair, and telomere maintenance. Furthermore, the authors highlight the targeting of macroH2A1.2 in ALT cells as a potentially effective means to halt tumor growth.