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Overcoming cellular senescence that is induced by telomere shortening is critical in tumorigenesis. A majority of cancers achieve telomere maintenance through telomerase expression. However, a subset of cancers takes an alternate route for elongating telomeres: recombination-based alternative lengthening of telomeres (ALT). Current evidence suggests that break-induced replication (BIR), independent of RAD51, underlies ALT telomere synthesis. However, RAD51-dependent homologous recombination is required for homology search and inter-chromosomal telomere recombination in human ALT cancer cell maintenance. Accumulating evidence suggests that the breakdown of stalled replication forks, the replication stress, induces BIR at telomeres. Nevertheless, ALT research is still in its early stage and a comprehensive view is still unclear. Here, we review the current findings regarding the genesis of ALT, how this recombinant pathway is chosen, the epigenetic regulation of telomeres in ALT, and perspectives for clinical applications with the hope that this overview will generate new questions. [Display omitted] • Alternative lengthening of telomeres involves multiple recombination pathways. • Break-induced replication is the central mechanism underlying ALT TMM. • Replication stress caused by G-quadruplex or R-loop triggers telomere recombination. • Epigenetic control is crucial for ALT activity. • ALT telomeres cluster and display properties of liquid-liquid phase separation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]