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RAD52 and SLX4 act nonepistatically to ensure telomere stability during alternative telomere lengthening.


Maximus Peto’s Commentary

I reported recently on another group’s findings about the relevance of RAD52 to ALT activity (see PMID 30673617). The current study appears to suggest that (1) RAD52 is involved in ALT activity, perhaps by its loss, and (2) SLX4 may be necessary for ALT, because its impairment at the same time as RAD52 deficiency “resulted in elevated telomere loss, unresolved telomere recombination intermediates, and mitotic infidelity.” But perhaps I’m misunderstanding this abstract.


RAD52 and SLX4 act nonepistatically to ensure telomere stability during alternative telomere lengthening.
Genes Dev. 2019 Feb 1;33(3-4):221-235.
Verma P, Dilley RL#, Zhang T#, Gyparaki MT, Li Y, Greenberg RA
DOI: 10.1101/gad.319723.118
PubMed publication date (edat): 1/30/2019

Abstract

Approximately 15% of cancers use homologous recombination for alternative lengthening of telomeres (ALT). How the initiating genomic lesions invoke homology-directed telomere synthesis remains enigmatic. Here, we show that distinct dependencies exist for telomere synthesis in response to replication stress or DNA double-strand breaks (DSBs). RAD52 deficiency reduced spontaneous telomeric DNA synthesis and replication stress-associated recombination in G2, concomitant with telomere shortening and damage. However, viability and proliferation remained unaffected, suggesting that alternative telomere recombination mechanisms compensate in the absence of RAD52. In agreement, RAD52 was dispensable for DSB-induced telomere synthesis. Moreover, a targeted CRISPR screen revealed that loss of the structure-specific endonuclease scaffold SLX4 reduced the proliferation of RAD52-null ALT cells. While SLX4 was dispensable for RAD52-mediated ALT telomere synthesis in G2, combined SLX4 and RAD52 loss resulted in elevated telomere loss, unresolved telomere recombination intermediates, and mitotic infidelity. These findings establish that RAD52 and SLX4 mediate distinct postreplicative DNA repair processes that maintain ALT telomere stability and cancer cell viability.

PMID: 30692206
Free Full-Text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362809/

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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