DNA replication: the recombination connection. Issue 1 (January 2022)

• Record Type: Journal Article
• Authors: Epum, Esther A.; Haber, James E.
• Is Part Of: Trends in cell biology. Volume 32:Issue 1(2022)
• Page Start: 45
• Page End: 57
• Publication Date: 2022-01
• Subjects: break-induced replication (BIR) -- alternative lengthening of telomeres (ALT) -- mitotic DNA synthesis (MiDAS) -- homologous recombination; Cytology -- Periodicals; Cytology -- Research -- Periodicals; 571.6
• DOI: 10.1016/j.tcb.2021.07.005
• Languages: English
• ISSNs: 0962-8924

Abstract

Abstract : Failure to complete DNA replication is one of the major sources of genome instability leading to aneuploidy, chromosome breakage, and chromosome rearrangements that are associated with human cancer. One of the surprising revelations of the past decade is that the completion of replication at so-called common fragile sites (CFS) occurs very late in the cell cycle – at mitosis – through a process termed MiDAS (mitotic DNA synthesis). MiDAS is strongly related to another cancer-promoting phenomenon: the activation of alternative lengthening of telomeres (ALT). Our understanding of the mechanisms of ALT and MiDAS in mammalian cells has drawn heavily from recent advances in the study of break-induced replication (BIR), especially in budding yeast. We provide new insights into the BIR, MiDAS, and ALT pathways and their shared similarities. Highlights: Break-induced replication (BIR) results in conservative DNA replication, where both strands of newly copied DNA are inherited together. Synthesis of the second strand is delayed, resulting in single-stranded intermediates that are subject to frequent mutation. New approaches for studying alternative lengthening of telomeres (ALT) provide insights into the mechanisms of homologous recombination-dependent telomere maintenance. Infection of mammalian cells by Kaposi's sarcoma-associated herpesvirus (KSHV) imposes BIR-like telomere maintenance even in telomerase-positive cells. The function of ALT-associated promyelocytic leukemia (PML) bodies in telomere maintenance can now be studied by artificially tethering chromosome ends in a phase-separated condensates lacking PML. These studies emphasize the role of SUMOylation of telomere-associated proteins. Surprisingly, completing DNA replication takes place after S phase, when cells have entered mitosis. Selective labeling of mitotic DNA synthesis (MiDAS) reveals that MiDAS occurs principally at cytologically identified common fragile sites (CFS).