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Brca2 abrogation engages with the alternative lengthening of telomeres via break-induced replication.


Maximus Peto’s Commentary

This group reports an association between loss of BRCA2 and ALT activity in a cell culture model with telomerase-null mouse cells, possibly by inducing break-induced replication (“BIR”).


Brca2 abrogation engages with the alternative lengthening of telomeres via break-induced replication.
FEBS J. 2019 May;286(10):1841-1858.
Kwon MS, Lee JJ, Min J, Hwang K, Park SG, Kim EH, Kim BC, Bhak J, Lee H
DOI: 10.1111/febs.14796
PubMed publication date (edat): 2/28/2019

Abstract

A subset of cancer cells maintains their telomeres without telomerase through the recombination-based alternative lengthening of telomeres (ALT) pathway. Currently, it is not yet clear in what context ALT is induced and how the pathway choice is made. Here, we show that abrogation of Brca2 reinforces break-induced replication (BIR) and engages with ALT pathway. Brca2 depletion in telomerase-null mouse cells alleviated the growth defect, accompanied by telomere elongation, suggesting the induction of ALT. We also found that Brca2-depleted telomerase-null cells exhibited dynamic clustering of telomeres from G2 phase in Promyelocytic Nuclear (PML) bodies. For Brca2-deficient ALT induction, Rad51 was dispensable but Mre11 and Rad52 were required. Congruently, conservative telomeric DNA synthesis was apparent in mitosis, indicating that the absence of Brca2 directed towards Rad52-mediated BIR. Collectively, we propose that Brca2 abrogation can instigate ALT tumourigenesis through the induction of BIR. This study implies that inhibitors of BIR may be useful for BRCA2-associated ALT-type cancers. Assessing ALT features may be considered for the tailored therapy of BRCA2-associated cancers.

PMID: 30811824
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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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