FIRRM/C1orf112 is synthetic lethal with PICH and mediates RAD51 dynamics

Stok, Colin; Tsaridou, Stavroula; van den Tempel, Nathalie; Everts, Marieke; Wierenga, Elles; Bakker, Femke J.; Kok, Yannick; Alves, Inês Teles; Jae, Lucas T.; Raas, Maximilian W.D.; Huis in 't Veld, Pim J.; de Boer, H. Rudolf; Bhattacharya, Arkajyoti; Karanika, Eleftheria; Warner, Harry; Chen, Mengting; van de Kooij, Bert; Dessapt, Julien; ter Morsche, Lars; Perepelkina, Polina; Fradet-Turcotte, Amelie; Guryev, Victor; Tromer, Eelco C.; Chan, Kok-Lung; Fehrmann, Rudolf S.N.; van Vugt, Marcel A.T.M.

doi:10.1016/j.celrep.2023.112668

Cited by 12 publications

(4 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These data reinforce the idea that PICH inhibition could be useful for other non- MYC -driven cancer types. Interestingly, a recent study has shown that PICH becomes more important for cell viability in cells deficient for DNA maintenance genes, such as those related to DNA repair, DNA condensation, centromere stability, and regulators of the replication fork stability such as FIRRM [ 42 ]. In addition, a recent study has found that PICH deficiency is synthetic lethal with SUMOylation inhibitors [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

PICH deficiency limits the progression of MYC-induced B-cell lymphoma

Castejón-Griñán,

Albers,

Simón-Carrasco

et al. 2024

Blood Cancer J.

View full text Add to dashboard Cite

Plk1-interacting checkpoint helicase (PICH) is a DNA translocase involved in resolving ultrafine anaphase DNA bridges and, therefore, is important to safeguard chromosome segregation and stability. PICH is overexpressed in various human cancers, particularly in lymphomas such as Burkitt lymphoma, which is caused by MYC translocations. To investigate the relevance of PICH in cancer development and progression, we have combined novel PICH-deficient mouse models with the Eμ-Myc transgenic mouse model, which recapitulates B-cell lymphoma development. We have observed that PICH deficiency delays the onset of MYC-induced lymphomas in Pich heterozygous females. Moreover, using a Pich conditional knockout mouse model, we have found that Pich deletion in adult mice improves the survival of Eμ-Myc transgenic mice. Notably, we show that Pich deletion in healthy adult mice is well tolerated, supporting PICH as a suitable target for anticancer therapies. Finally, we have corroborated these findings in two human Burkitt lymphoma cell lines and we have found that the death of cancer cells was accompanied by chromosomal instability. Based on these findings, we propose PICH as a potential therapeutic target for Burkitt lymphoma and for other cancers where PICH is overexpressed.

show abstract

Section: Discussionmentioning

confidence: 99%

PICH deficiency limits the progression of MYC-induced B-cell lymphoma

Castejón-Griñán,

Albers,

Simón-Carrasco

et al. 2024

Blood Cancer J.

View full text Add to dashboard Cite

show abstract

“…The eukaryotic sequence database used for the evolutionary analysis consisted of 177 predicted proteomes derived from genomes or transcriptomes and spans a representative set of species across the eukaryotic tree of life. This dataset is derived from earlier work ( Potter et al, 2023 , Preprint ), with some minor adjustments detailed in Stok et al (2023) .…”

Section: Methodsmentioning

confidence: 99%

A farnesyl-dependent structural role for CENP-E in expansion of the fibrous corona

Wu,

Raas,

Alcaraz

et al. 2023

Journal of Cell Biology

Self Cite

View full text Add to dashboard Cite

Correct chromosome segregation during cell division depends on proper connections between spindle microtubules and kinetochores. During prometaphase, kinetochores are temporarily covered with a dense protein meshwork known as the fibrous corona. Formed by oligomerization of ROD/ZW10/ZWILCH-SPINDLY (RZZ-S) complexes, the fibrous corona promotes spindle assembly, chromosome orientation, and spindle checkpoint signaling. The molecular requirements for formation of the fibrous corona are not fully understood. Here, we show that the fibrous corona depends on the mitotic kinesin CENP-E and that poorly expanded fibrous coronas after CENP-E depletion are functionally compromised. This previously unrecognized role for CENP-E does not require its motor activity but instead is driven by farnesyl modification of its C-terminal kinetochore- and microtubule-binding domain. We show that in cells, CENP-E binds Spindly and recruits RZZ-S complexes to ectopic locations in a farnesyl-dependent manner. CENP-E is recruited to kinetochores following RZZ-S, and—while not required for RZZ-S oligomerization per se—promotes subsequent fibrous corona expansion. Our comparative genomics analyses suggest that the farnesylation motif in CENP-E orthologs emerged alongside the full RZZ-S module in an ancestral lineage close to the fungi–animal split (Obazoa), revealing potential conservation of the mechanisms for fibrous corona formation. Our results show that proper spindle assembly has a potentially conserved non-motor contribution from the kinesin CENP-E through stabilization of the fibrous corona meshwork during its formation.

show abstract

“…This dataset contains the protein sequences of phylogenetically diverse eukaryotes, and model organisms. For this project, we modified the dataset as described before 44 . An overview of the included species can be found in Supplementary Table 1, where we also report the proteome completeness scores derived from BUSCO 45 .…”

Section: Eukaryotic Dataset Assemblymentioning

confidence: 99%

Shaping up genomes: Prokaryotic roots and eukaryotic diversification of SMC complexes

van Hooff,

Raas,

Tromer

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Across the tree of life, SMC complexes organize, segregate and regulate DNA. In contrast to prokaryotes, which often possess one SMC complex, eukaryotes usually have four such complexes. This expanded set is involved in managing the considerably larger nuclear genomes of eukaryotes, which are distributed across multiple chromosomes. Despite their essential functions, SMC complexes exhibit variations across model eukaryotes, suggesting an even greater variety of these complexes that remains unexplored. Here, we aimed to uncover the diversity and evolution of SMC complexes across eukaryotes, and their deeper, prokaryotic evolutionary origins. For this, we conducted in-depth comparative genomic and phylogenetic analyses of SMC complexes. We show that the last eukaryotic common ancestor (LECA) likely had fully-fledged versions of all four complexes and that the condensin II complex was later lost at least 30 times in eukaryotes. We report evidence that proteins previously designated as functional analogs in various model organisms (e.g., Sororin, Securin, Nse5 and Nse6) are in fact genuine orthologs. Finally, we traced the prokaryotic origins of these complexes and propose that a single SMC complex duplicated in an early archaeon. Altogether, we provide a comprehensive overview of eukaryotic SMC complex diversity and evolution, both addressing and generating questions about their functioning in ancestral and contemporary organisms.

show abstract

FIRRM/C1orf112 is synthetic lethal with PICH and mediates RAD51 dynamics

Cited by 12 publications

References 87 publications

PICH deficiency limits the progression of MYC-induced B-cell lymphoma

PICH deficiency limits the progression of MYC-induced B-cell lymphoma

A farnesyl-dependent structural role for CENP-E in expansion of the fibrous corona

Shaping up genomes: Prokaryotic roots and eukaryotic diversification of SMC complexes

Contact Info

Product

Resources

About