Brca2 abrogation engages with the alternative lengthening of telomeres via break‐induced replication. (12th March 2019)

• Record Type: Journal Article
• Authors: Kwon, Mi‐Sun; Lee, Jennifer J.; Min, Jaewon; Hwang, Kwangwoo; Park, Seung Gu; Kim, Eun‐Hye; Kim, Byung Chul; Bhak, Jong; Lee, Hyunsook
• Is Part Of: FEBS journal. Volume 286:Number 10(2019)
• Page Start: 1841
• Page End: 1858
• Publication Date: 2019-03-12
• Subjects: ALT mouse -- alternative lengthening of telomeres -- Brca2 -- break‐induced replication; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.14796
• Languages: English
• ISSNs: 1742-464X

Abstract

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. Abstract : Cancer cells activate telomerase to avoid shortening of their telomeres, enabling indefinite DNA replication. However, about 10% of cancer cells do not express telomerase and maintain their telomeres through the recombination‐based alternative lengthening of telomeres (ALT) pathway. Currently, the mechanisms underlying ALT induction are not clear. Here, Hyunsook Lee and colleagues show that Brca2 depletion in telomerase‐null cells induces ALT by reinforcing break‐induced replication (BIR). Rad51 is dispensable for ALT induction in these cells while Rad52 and Mre11 are required, indicating that Brca2 abrogation directs towards Rad52‐mediated BIR. These results suggest that BIR inhibitors could be beneficial for BRCA2‐associated ALT cancers.