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Alternative Lengthening of Telomeres through Two Distinct Break-Induced Replication Pathways.


Maximus Peto’s Commentary

From my brief time working on the SRF OncoSENS project about ALT in 2012, I recall discussions about whether ALT activity may be induced by a gain-of-function change, or a loss-of-function change. The authors of this paper suggest that C-circle activity appears to be regulated by more than one pathway. At least in this model, ALT activity required RAD52 activity, but this pathway is not necessary for C-circle formation. Knocking out RAD52 in ALT cells could cause a gradual shortening of telomeres, but C-circles can still be formed. ALT cell DNA synthesis could also increase as telomeres shortened, but it’s not clear to me whether this meant that telomeres could still be maintained without RAD52.


Alternative Lengthening of Telomeres through Two Distinct Break-Induced Replication Pathways.
Cell Rep. 2019 Jan 22;26(4):955-968.e3.
Zhang JM, Yadav T, Ouyang J, Lan L, Zou L
DOI: 10.1016/j.celrep.2018.12.102
PubMed publication date (edat): 1/24/2019

Abstract

Alternative lengthening of telomeres (ALT) is a telomerase-independent but recombination-dependent pathway that maintains telomeres. Here, we describe an assay to visualize ALT-mediated telomeric DNA synthesis in ALT-associated PML bodies (APBs) without DNA-damaging agents or replication inhibitors. Using this assay, we find that ALT occurs through two distinct mechanisms. One of the ALT mechanisms requires RAD52, a protein implicated in break-induced DNA replication (BIR). We demonstrate that RAD52 directly promotes telomeric D-loop formation in vitro and is required for maintaining telomeres in ALT-positive cells. Unexpectedly, however, RAD52 is dispensable for C-circle formation, a hallmark of ALT. In RAD52-knockout ALT cells, C-circle formation and RAD52-independent ALT DNA synthesis gradually increase as telomeres are shortened, and these activities are dependent on BLM and BIR proteins POLD3 and POLD4. These results suggest that ALT occurs through a RAD52-dependent and a RAD52-independent BIR pathway, revealing the bifurcated framework and dynamic nature of this process.

PMID: 30673617
Free Full-Text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366628/

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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