Alternative Lengthening of Telomeres is a Self-Perpetuating Process in ALT-Associated PML Bodies
TL;DR: In this paper, a self-perpetuating process of break-induced replication (BIR) at telomeres is investigated, and it is shown that BIR generates replication stress.
About: This article is published in Molecular Cell.The article was published on 2021-03-04. It has received 42 citations till now. The article focuses on the topics: Telomere.
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TL;DR: The current understanding of the sources of R-loops and RNA-DNA hybrids, mechanisms that suppress and resolve these structures, the impact of these structures on DNA repair and genome stability, and opportunities to therapeutically target pathological R-Loops are discussed.
44 citations
TL;DR: A review on the major sources of replication stress, the impacts of DNA replication stress in cells, and the assays to detect replication stress can be found in this paper , which provides an overview of the hallmarks of the replication stress.
42 citations
TL;DR: Understanding of the cellular and pathophysiological roles of SUMO modifications is increased, extending their functions to the regulation of immunity, pluripotency and nuclear body assembly in response to oxidative stress, which partly occurs through the recently characterized mechanism of liquid–liquid phase separation.
39 citations
TL;DR: This Review discusses the mechanistic differences between telomere maintenance by telomerase and ALT, the current methods used to detect each mechanism, the utility of these tests for clinical diagnosis, and recent developments in the therapeutic strategies being employed to target both telomersase andALT.
38 citations
TL;DR: In this paper, the authors provide new insights into the break-induced replication (BIR), MiDAS, and ALT pathways and their shared similarities, including the activation of alternative lengthening of telomeres (ALT).
25 citations
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TL;DR: The data suggest a conceptual framework for considering the composition and control of cellular bodies assembled through heterotypic multivalent interactions, suggesting how their compositions could be controlled by levels of PML SUMOylation or cellular mRNA concentration, respectively.
854 citations
Journal Article•
TL;DR: It is reported here that ALT cells contain a novel promyelocytic leukemia (PML) body (ALT-associated PML body, APB), which are large donut-shaped nuclear structures containing PML protein, telomeric DNA, and the telomere binding proteins human telomerre repeat binding factors 1 and 2.
Abstract: Telomerase-negative immortalized human cells maintain their telomeres by a mechanism known as alternative lengthening of telomeres (ALT). We report here that ALT cells contain a novel promyelocytic leukemia (PML) body (ALT-associated PML body, APB). APBs are large donut-shaped nuclear structures containing PML protein, telomeric DNA, and the telomere binding proteins human telomere repeat binding factors 1 and 2. Immunostaining showed that APBs also contain replication factor A, RAD51, and RAD52, proteins involved in DNA synthesis and recombination. During immortalization, APBs appeared at exactly the same time as activation of ALT. APBs were found in ALT tumors and cell lines but not in mortal cell strains or in telomerase-positive cell lines or tumors.
677 citations
TL;DR: Proteomics of isolated chromatin segments (PICh) is described, identifying and validated several proteins that specifically bind to ALT telomeres, establishing PICh as a useful tool for characterizing chromatin composition.
498 citations
TL;DR: It is demonstrated that PML contains a SUMO binding motif that is independent of its SUMOylation sites and is surprisingly necessary for PML-NB formation, and it is proposed that the PML RING domain is critical forPML SUMoylation and PML -NB formation.
475 citations
TL;DR: The data on the known PML isoforms and splice variants are summarized and a new unifying nomenclature is presented, suggesting that these sequences are indispensable for function, but differ in their C-terminal sequences.
Abstract: PML is a component of a multiprotein complex, termed nuclear bodies, and the PML protein was originally discovered in patients suffering from acute promyelocytic leukaemia (APL). APL is associated with a reciprocal chromosomal translocation of chromosomes 15 and 17, which results in a fusion protein comprising PML and the retinoic acid receptor alpha. The PML genomic locus is approximately 35 kb and is subdivided into nine exons. A large number of alternative spliced transcripts are synthesized from the PML gene, resulting in a variety of PML proteins ranging in molecular weight from 48-97 kDa. In this review we summarize the data on the known PML isoforms and splice variants and present a new unifying nomenclature. Although, the function/s of the PML variants are unclear, all PML isoforms contain an identical N-terminal region, suggesting that these sequences are indispensable for function, but differ in their C-terminal sequences. The N-terminal region harbours a RING-finger, two B-boxes and a predicted alpha-helical Coiled-Coil domain, that together form the RBCC/TRIM motif found in a large family of proteins. In PML this motif is essential for PML nuclear body formation in vivo and PML-homo and hetero interactions conferring growth suppressor, apoptotic and anti-viral activities. In APL oligomerization mediated by the RBCC/TRIM motif is essential for the transformation potential of the PML-RARalpha fusion protein.
473 citations