Mitotic regulators TPX2 and Aurora A protect DNA forks during replication stress by counteracting 53BP1 function

Byrum, Andrea K.; Carvajal-Maldonado, Denisse; Mudge, Miranda C.; Valle-García, David; Majid, Mona C.; Patel, Romil; Sowa, Mathew E.; Gygi, Steven P.; Harper, J. Wade; Shi, Yang; Vindigni, Alessandro; Mosammaparast, Nima

doi:10.1083/jcb.201803003

Cited by 44 publications

(58 citation statements)

References 30 publications

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“…Moreover, (Byrum et al, 2019;Cantor, 2019) identified an interaction between TP53BP1 and TPX2, as well as its kinase partner Aurora A, during mitosis.…”

Section: Discussionmentioning

confidence: 99%

TP53BP1 regulates chromosome alignment and spindle bipolarity in mouse oocytes

Jin

Namgoong

2019

Molecular Reproduction Devel

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Meiotic oocytes lack classic centrosomes; therefore, bipolar spindle assembly depends on the clustering of acentriolar microtubule‐organizing centers (MTOCs) into two poles. The bipolar spindle is an essential cellular component that ensures accurate chromosome segregation during anaphase. If the spindle does not form properly, it can result in aneuploidy or cell death. However, the molecular mechanism by which the bipolar spindle is established is not yet fully understood. Tumor suppressor p53‐binding protein 1 (TP53BP1) is known to mediate the DNA damage response. Several recent studies have indicated that TP53BP1 has noncanonical roles in processes, such as spindle formation; however, the role of TP53BP1 in oocyte meiosis is currently unclear. Our results show that TP53BP1 knockdown affects spindle bipolarity and chromatin alignment by altering MTOC stability during oocyte maturation. TP53BP1 was localized in the cytoplasm and displayed an irregular cloud pattern around the spindle/chromosome region. TP53BP1 was also required for the correct localization of MTOCs into the two spindle poles during pro‐meiosis I. TP53BP1 deletion altered the MTOC‐localized Aurora Kinase A. TP53BP1 knockdown caused the microtubules to detach from the kinetochores and increased the rate of aneuploidy. Taken together, our data show that TP53BP1 plays crucial roles in chromosome stability and spindle bipolarity during meiotic maturation.

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“…Moreover, (Byrum et al, 2019;Cantor, 2019) identified an interaction between TP53BP1 and TPX2, as well as its kinase partner Aurora A, during mitosis.…”

Section: Discussionmentioning

confidence: 99%

TP53BP1 regulates chromosome alignment and spindle bipolarity in mouse oocytes

Jin

Namgoong

2019

Molecular Reproduction Devel

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“…Complex (APC/C) ubiquitin ligase at mitotic exit 18,19 . However, AURKA is detectable in interphase cells and has been attributed a number of non-mitotic roles including ciliation control, cell cycle regulation of MYCNdependent transcription, DNA damage pathways and mitochondrial regulation [20][21][22][23] . Overall, there is a growing interest in the roles played by AURKA outside of mitosis and their contribution to its cancerpromoting activity.…”

Section: Aurka Undergoes Targeted Proteolysis In Every Cell Cycle Asmentioning

confidence: 99%

Selective targeting of non-centrosomal AURKA functions through use of a targeted protein degradation tool

Wang

Abdelbaki

Ascanelli

et al. 2020

Preprint

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Targeted protein degradation tools are becoming a new therapeutic modality, allowing small molecule ligands to be reformulated as heterobifunctional molecules (referred to as ‘PROTACs’, for PROteolysis Targeting Chimeras) that recruit a ubiquitin ligase to the target of interest, leading to ubiquitination of the target and its destruction via the ubiquitin-proteasome system. A number of PROTACs against targets of clinical interest have been described, but detailed descriptions of the cell biology modulated by PROTACs are missing from the literature. Here we describe the functional characterization of a PROTAC derived from AURKA inhibitor MLN8237 (alisertib). We demonstrate efficient and specific destruction of both endogenous and overexpressed AURKA by Cereblon-directed PROTACs. At the subcellular level, we find differential targeting of AURKA on the mitotic spindle compared to centrosomes. The phenotypic consequences of PROTAC treatment are therefore distinct from those mediated by alisertib, and in mitotic cells differentially regulate the centrosome- and chromatin-based microtubule spindle assembly pathways. In interphase cells we find that PROTAC-mediated clearance of non-centrosomal AURKA, and not PROTAC-mediated inhibition of its activity, efficiently modulates the cytoplasmic role played by AURKA in mitochondrial dynamics, whilst the centrosomal pool is refractory to PROTAC-mediated clearance. Our results point to differential accessibility of subcellular pools of substrate, governed by substrate conformation or localization in compartments more or less accessible to PROTAC action, a phenomenon not previously described for this new class of drugs.

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“…Recent studies of the effects of acute inhibition of AURKA during mitosis have concluded that it plays an important role during mitotic exit in regulating assembly of the anaphase spindle upon which sister chromatids are segregated [3][4][5]. AURKA also has a number of non-mitotic roles that include disassembly of the primary cilium, regulation of myc family transcription factors and response to replication stress [6][7][8][9][10]. We and others recently reported that AURKA constitutively regulates mitochondrial morphology and function [11,12] in addition to a previously reported role in promoting mitochondrial fission in mitosis [13].…”

Section: Introductionmentioning

confidence: 99%

AURKA destruction is decoupled from its activity at mitotic exit but suppresses interphase activity

Abdelbaki

Akman

Poteau³

et al. 2019

Preprint

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Activity of AURKA is controlled through multiple mechanisms including phosphorylation, ubiquitinmediated degradation, and allosteric interaction with TPX2. Activity peaks at mitosis before AURKA is degraded during mitotic exit in a process strictly dependent on APC/C coactivator FZR1. We used FZR1 knockout cells (FZR1 KO ) and a novel FRET-based AURKA biosensor to investigate how activity is regulated in absence of destruction. We found that AURKA activity in FZR1 KO cells dropped at mitotic exit as rapidly as in parental cells, despite absence of destruction. Unexpectedly, TPX2 was degraded normally in FZR1 KO cells. Overexpression of an N-terminal TPX2 fragment sufficient for AURKA binding, but not degraded at mitotic exit, caused delay in AURKA inactivation. We conclude that AURKA inactivation in mitotic exit is determined not by its own degradation but by degradation of TPX2 and therefore dependent on CDC20 rather than FZR1. The biosensor revealed that FZR1 instead suppresses AURKA activity in interphase and is critically required for assembly of the interphase mitochondrial network after mitosis.

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Mitotic regulators TPX2 and Aurora A protect DNA forks during replication stress by counteracting 53BP1 function

Cited by 44 publications

References 30 publications

TP53BP1 regulates chromosome alignment and spindle bipolarity in mouse oocytes

TP53BP1 regulates chromosome alignment and spindle bipolarity in mouse oocytes

Selective targeting of non-centrosomal AURKA functions through use of a targeted protein degradation tool

AURKA destruction is decoupled from its activity at mitotic exit but suppresses interphase activity

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