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
PubMed publication date (edat): 1/30/2019
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.
Free Full-Text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362809/