Consequences of telomere replication failure: the other end-replication problem. Issue 6 (June 2022)

• Record Type: Journal Article
• Authors: Brenner, Kirsten A.; Nandakumar, Jayakrishnan
• Is Part Of: Trends in biochemical sciences. Volume 47:Issue 6(2022)
• Page Start: 506
• Page End: 517
• Publication Date: 2022-06
• Subjects: telomeres -- replication stress -- break-induced replication -- mitotic DNA synthesis -- alternative lengthening of telomeres; Biochemistry -- Periodicals; 572
• DOI: 10.1016/j.tibs.2022.03.013
• Languages: English
• ISSNs: 0968-0004

Abstract

Abstract : Telomeres are chromosome-capping structures that protect ends of the linear genome from DNA damage sensors. However, these structures present obstacles during DNA replication. Incomplete telomere replication accelerates telomere shortening and limits replicative lifespan. Therefore, continued proliferation under conditions of replication stress requires a means of telomere repair, particularly in the absence of telomerase. It was recently revealed that replication stress triggers break-induced replication (BIR) and mitotic DNA synthesis (MiDAS) at mammalian telomeres; however, these mechanisms are error prone and primarily utilized in tumorigenic contexts. In this review article, we discuss the consequences of replication stress at telomeres and how use of available repair pathways contributes to genomic instability. Current research suggests that fragile telomeres are ultimately tumor-suppressive and thus may be better left unrepaired. Highlights: Telomeres are prone to replication fork stalling and collapse when subjected to replication stress, and failure to complete telomere replication accelerates telomere shortening and limits replicative lifespan. Telomere replication after fork collapse can resume via break-induced replication (BIR) and mitotic DNA synthesis (MiDAS); however, recent findings indicate that these pathways are error prone and associated with genomic instability and tumorigenesis. BIR and MiDAS at telomeres are more prevalent in cancer cells and are suppressed by cell cycle checkpoints, implicating telomere fragility under replication stress as a tumor-suppressive mechanism. Further characterization of BIR-mediated telomere synthesis in different cell types should provide insight into the molecular basis of tumorigenesis, particularly regarding activation of alternative lengthening of telomeres (ALT).