CIP2A Interacts with TopBP1 and Drives Basal-Like Breast Cancer Tumorigenesis

Laine, Antti; Nagelli, Srikar G.; Farrington, Caroline; Butt, Umar; Cvrljevic, Anna N.; Vainonen, Julia P.; Feringa, Femke M.; Grönroos, Tove J.; Gautam, Prson; Khan, Sofia; Sihto, Harri; Qiao, Xi; Pavic, Karolina; Connolly, Denise C.; Kronqvist, Pauliina; Elo, Laura L.; Maurer, Jochen; Wennerberg, Krister; Medema, René H.; Joensuu, Heikki; Peuhu, Emilia; Visser, Karin E. de; Narla, Goutham; Westermarck, Jukka

doi:10.1158/0008-5472.can-20-3651

Cited by 28 publications

(29 citation statements)

References 53 publications

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“…Surprisingly, deletion of the longer, more C-terminal conserved patch alone (aa 813-892) also completely abrogated recruitment of TOPBP1 to sites of damage, while its interaction with CIP2A was only partially defective. This is somewhat in conflict with two recently published studies in which yeast-two-hybrid analysis was used to map the CIP2A interaction site in TOPBP1 to amino acids 830–852 17 , 18 . An explanation for this discrepancy may be the different assays used.…”

Section: Discussioncontrasting

confidence: 66%

“…We previously identified this protein in a proteomic screen for interaction partners of full-length TOPBP1 15 . Moreover, it was also identified in a proximity proteomic screen for BRCA1-interacting factors along with TOPBP1 16 and it was recently shown to interact with TOPBP1 by yeast-two-hybrid assays and co-immonoprecipitation 17 , 18 . CIP2A is a 905 amino acid protein, roughly composed of two structurally distinct regions: a N-terminal Armadillo repeat domain (ArmRD; amino acids 1–560) and a C-terminal predicted coiled-coil region (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

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The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis

et al. 2022

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The accurate repair of DNA double-strand breaks (DSBs), highly toxic DNA lesions, is crucial for genome integrity and is tightly regulated during the cell cycle. In mitosis, cells inactivate DSB repair in favor of a tethering mechanism that stabilizes broken chromosomes until they are repaired in the subsequent cell cycle phases. How this is achieved mechanistically is not yet understood, but the adaptor protein TOPBP1 is critically implicated in this process. Here, we identify CIP2A as a TOPBP1-interacting protein that regulates TOPBP1 localization specifically in mitosis. Cells lacking CIP2A display increased radio-sensitivity, micronuclei formation and chromosomal instability. CIP2A is actively exported from the cell nucleus in interphase but, upon nuclear envelope breakdown at the onset of mitosis, gains access to chromatin where it forms a complex with MDC1 and TOPBP1 to promote TOPBP1 recruitment to sites of mitotic DSBs. Collectively, our data uncover CIP2A-TOPBP1 as a mitosis-specific genome maintenance complex.

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Section: Discussioncontrasting

confidence: 66%

Section: Resultsmentioning

confidence: 99%

The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis

et al. 2022

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“…TOPBP1 is known to be recruited to some DNA damage lesions in mitosis through direct interaction with MDC1 27 , which in turn directly binds to the mega-base domains of γ H2AX-containing chromatin assembled at DSBs 18 . CIP2A interacts with TOPBP1 and mediates its recruitment to DNA damage sites in mitosis 26,28,29 . Both ruptured and intact micronuclei have abnormal nucleoplasm (in the latter case as a consequence of deficient nuclear import 9,30 ) and during interphase they fail to recruit key DNA repair proteins, including 53BP1 and BRCA1, even after DNA damage marked by γ H2AX ( Extended Data Fig.…”

Section: Resultsmentioning

confidence: 99%

Mitotic tethering enables en masse inheritance of a shattered micronuclear chromosome

Cleveland

Trivedi

Steele

et al. 2022

Preprint

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Chromothripsis, the shattering and imperfect reassembly of one (or a few) chromosome(s)1, is an ubiquitous2 mutational process generating localized complex chromosomal rearrangements that drive genome evolution in cancer. Chromothripsis can be initiated by missegregation errors in mitosis3,4 or DNA metabolism5-7 that lead to entrapment of chromosomes within micronuclei and their subsequent fragmentation in the next interphase or upon mitotic entry6,8-10. Here, we use inducible degrons to demonstrate that chromothriptically produced pieces of a micronucleated chromosome are tethered together in mitosis by a protein complex consisting of Mediator of DNA damage checkpoint 1 (MDC1), DNA Topoisomerase II Binding Protein 1 (TOPBP1), and Cellular Inhibitor of PP2A (CIP2A), thereby enabling en masse segregation to the same daughter cell. Such tethering is shown to be crucial for the viability of cells undergoing chromosome missegregation and shattering after transient inactivation of the spindle assembly checkpoint. Pan-cancer analysis of transcriptome and whole-genome sequencing data revealed that chromothriptic genome rearrangements were accompanied by elevated expression of MDC1, TOPBP1, and CIP2A. Thus, chromatin-bound tethers maintain proximity of fragments of a shattered chromosome enabling their re-encapsulation into, and religation within, a daughter cell nucleus to form heritable, chromothriptically rearranged chromosomes found in the majority of human cancers.

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“…The observations that ATR phosphorylation was reduced in USP13-deficient cells and can be restored by recombinant expression of TopBP1 established that USP13 can regulate DNA replication stress by controlling the degradation of the TopBP1. Importantly, TopBP1 is proved to be correlated with multiple cancers and exerts roles in chemotherapy resistance ( Forma et al, 2012 ; Chowdhury et al, 2014 ; Lv et al, 2016 ; Liu et al, 2021c ; Laine et al, 2021 ). Moreover, incubation with USP13 inhibitor spautin-1 reduces survival of OVCA cell lines after replication stress inducing agents, implying that the development of selective USP13 inhibitors is feasible for treatment of these patients of conventional cancer chemotherapy ( Kim et al, 2021 ).…”

Section: Cellular Function Of Usp13mentioning

confidence: 99%

USP13: Multiple Functions and Target Inhibition

Yang

Zhang

et al. 2022

Front. Cell Dev. Biol.

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As a deubiquitination (DUB) enzyme, ubiquitin-specific protease 13 (USP13) is involved in a myriad of cellular processes, such as mitochondrial energy metabolism, autophagy, DNA damage response, and endoplasmic reticulum-associated degradation (ERAD), by regulating the deubiquitination of diverse key substrate proteins. Thus, dysregulation of USP13 can give rise to the occurrence and development of plenty of diseases, in particular malignant tumors. Given its implications in the stabilization of disease-related proteins and oncology targets, considerable efforts have been committed to the discovery of inhibitors targeting USP13. Here, we summarize an overview of the recent advances of the structure, function of USP13, and its relations to diseases, as well as discovery and development of inhibitors, aiming to provide the theoretical basis for investigation of the molecular mechanism of USP13 action and further development of more potent druggable inhibitors.

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CIP2A Interacts with TopBP1 and Drives Basal-Like Breast Cancer Tumorigenesis

Abstract: Running title: CIP2A drives basal-like breast cancers via TopBP1 and MYC Research.

Cited by 28 publications

References 53 publications

The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis

The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis

Mitotic tethering enables en masse inheritance of a shattered micronuclear chromosome

USP13: Multiple Functions and Target Inhibition

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