The BUB3-BUB1 Complex Promotes Telomere DNA Replication

Li, Feng; Kim, Hyeung; Ji, Zhejian; Zhang, Tianpeng; Chen, Bohong; Ge, Yuanlong; Hu, Yang; Feng, Xuyang; Han, Xin; Xu, Huimin; Zhang, Youwei; Yu, Hongtao; Liú, Dan; Ma, Wenbin; Songyang, Zhou

doi:10.1016/j.molcel.2018.03.032

Cited by 63 publications

(48 citation statements)

References 89 publications

(139 reference statements)

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“…Refining our artificially engineered system to more closely reflect in vivo events, thus allowing continuous cell proliferation, will provide further insight into APB formation and the ALT pathway. BLM protein has been implicated in the ALT pathway as well as telomere replication processes (Sfeir et al 2009;Barefield and Karlseder 2012;Zimmermann et al 2014;Li et al 2018). In the present studies, we demonstrated that BLM helicase is required for the initiation of telomere clustering and telomeric MiDAS through its helicase activity by cooperating with DNA2, which is responsible for the generation of single-stranded telomeric DNAs via long-range resection processes.…”

Section: Discussionsupporting

confidence: 56%

Clustered telomeres in phase-separated nuclear condensates engage mitotic DNA synthesis through BLM and RAD52

2019

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Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that occurs in a subset of cancers. One of the hallmarks of ALT cancer is the excessively clustered telomeres in promyelocytic leukemia (PML) bodies, represented as large bright telomere foci. Here, we present a model system that generates telomere clustering in nuclear polySUMO (small ubiquitin-like modification)/polySIM (SUMO-interacting motif) condensates, analogous to PML bodies, and thus artificially engineered ALT-associated PML body (APB)-like condensates in vivo. We observed that the ALT-like phenotypes (i.e., a small fraction of heterogeneous telomere lengths and formation of C circles) are rapidly induced by introducing the APB-like condensates together with BLM through its helicase domain, accompanied by ssDNA generation and RPA accumulation at telomeres. Moreover, these events lead to mitotic DNA synthesis (MiDAS) at telomeres mediated by RAD52 through its highly conserved N-terminal domain. We propose that the clustering of large amounts of telomeres in human cancers promotes ALT that is mediated by MiDAS, analogous to Saccharomyces cerevisiae type II ALT survivors.

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Section: Discussionsupporting

confidence: 56%

Clustered telomeres in phase-separated nuclear condensates engage mitotic DNA synthesis through BLM and RAD52

2019

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“…Bub1-mediated H2ApT120 is sufficient to recruit TOP2A to centromeres and to a non-centromeric chromatin region So far, only a few substrates of Bub1 have been identified, including the anaphase-promoting complex/cyclosome (APC/C) co-activator Cdc20 (Tang et al, 2004;Jia et al, 2016), histone H2A (Kawashima (Li et al, 2018). Among them, histone H2A is the best characterized substrate in vivo.…”

Section: Resultsmentioning

confidence: 99%

“…The EMBO Journal 39: e101863 | 2020 ª 2019 The Authors et al, 2010), and the telomere protein TRF1 (Li et al, 2018). Among them, histone H2A is the best characterized substrate in vivo.…”

Section: Bub1 Kinase Activity Is Necessary For Top2a Localization Atmentioning

confidence: 99%

Histone H2A phosphorylation recruits topoisomerase II α to centromeres to safeguard genomic stability

et al. 2019

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Chromosome segregation in mitosis requires the removal of catenation between sister chromatids. Timely decatenation of sister DNAs at mitotic centromeres by topoisomerase IIa (TOP2A) is crucial to maintain genomic stability. The chromatin factors that recruit TOP2A to centromeres during mitosis remain unknown. Here, we show that histone H2A Thr-120 phosphorylation (H2ApT120), a modification generated by the mitotic kinase Bub1, is necessary and sufficient for the centromeric localization of TOP2A. Phosphorylation at residue-120 enhances histone H2A binding to TOP2A in vitro. The C-gate and the extreme C-terminal region are important for H2ApT120-dependent localization of TOP2A at centromeres. Preventing H2ApT120mediated accumulation of TOP2A at mitotic centromeres interferes with sister chromatid disjunction, as evidenced by increased frequency of anaphase ultra-fine bridges (UFBs) that contain catenated DNA. Tethering TOP2A to centromeres bypasses the requirement for H2ApT120 in suppressing anaphase UFBs. These results demonstrate that H2ApT120 acts as a landmark that recruits TOP2A to mitotic centromeres to decatenate sister DNAs. Our study reveals a fundamental role for histone phosphorylation in resolving centromere DNA entanglements and safeguarding genomic stability during mitosis.MZ designed and performed the majority of the experiments and analysis. CL designed and carried out the GST pulldown assays (Figs 3E and F, and 6L), the localization of TOP2A in HeLa and Sgo1-K492A cells (Fig 4C and D), the competitive localization of EGFP-TOP2A and Sgo1 (Fig 7A-D), as well as the deconvolution microscopy (Appendix Fig S4). HZ and SL helped express the GST-H2ApS120 protein. XY performed the experiments shown in Appendix Fig S1. QC, HY, JX, and JL provided technical assistance. WL provided reagents and constructive suggestions. FW conceived and supervised the project, designed the experiments, analyzed the data, and wrote the manuscript with the input from HY.

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“…Therefore, the replication stress observed in K243R/+ and K243R/+; p53-/- MEFs may be a more direct result of the loss of BubR1 acetylation than from aneuploidy. Interestingly, a recent report showed that Bub1-Bub3, components of the mitotic checkpoint that interact with BubR1, promotes telomere replication in S phase (39). Therefore, there is a possibility that the defect in BubR1 acetylation may have affected the integrity of Bub3-Bub1 in S phase telomere replication fidelity.…”

Section: Discussionmentioning

confidence: 99%

Loss of BubR1 Acetylation instigates Replication Stress leading to Complex Chromosomal Rearrangement in tumors

Park

Yeu

Paik

et al. 2019

Preprint

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Chromosome number and structure instability is the hallmark of cancer. Equal chromosome segregation is guaranteed by the spindle assembly checkpoint (SAC), thus defective SAC leads to chromosome instability. However, aneuploidy alone is not oncogenic, and whether compromised SAC is associated with structure instability remains elusive. BubR1 is a core component of SAC, which is acetylated at lysine 250 in mitosis. Previously, we showed that deficiency of BubR1 acetylation in mice (K243R/+) leads to spontaneous tumorigenesis via chromosome mis-segregation. Here, we asked whether loss of BubR1 acetylation is associated with chromosome structure instability by examiningK243R/+mice intercrossed top53-deficient mice. Genome-wide sequencing and spectral karyotyping of the double mutant mouse tumors revealed that BubR1 acetylation deficiency leads to complex chromosome rearrangements, including Robertsonian-like whole-arm translocations and premature sister-chromatid separations (PMSCS). In primary MEFs, replication stress was markedly increased in telomeres and centromeres, suggesting that the replication stress underlies the significant increase of DNA damage and subsequent chromosome rearrangements. Furthermore, defects in BubR1 acetylation at K250 were detected in human cancers as well. Collectively, we propose that chromosome mis-segregation by the loss of BubR1 acetylation causes chromosome structure instability, leading to massive chromosome rearrangements through the induction of replication stress.

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The BUB3-BUB1 Complex Promotes Telomere DNA Replication

Cited by 63 publications

References 89 publications

Clustered telomeres in phase-separated nuclear condensates engage mitotic DNA synthesis through BLM and RAD52

Clustered telomeres in phase-separated nuclear condensates engage mitotic DNA synthesis through BLM and RAD52

Histone H2A phosphorylation recruits topoisomerase II α to centromeres to safeguard genomic stability

Loss of BubR1 Acetylation instigates Replication Stress leading to Complex Chromosomal Rearrangement in tumors

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