CSAG1 maintains the integrity of the mitotic centrosome in cells with defective p53

Sapkota, Hem; Wren, Jonathan D.; Gorbsky, Gary J.

doi:10.1242/jcs.239723

Cited by 8 publications

(6 citation statements)

References 42 publications

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“…Thus, genes in the MAGE-CSAG Xq28 gene cluster are functionally linked, similar to bacterial operons. Consistent with this idea, CSAG1 has been suggested to promote mitotic progression specifically in p53 defective tumor cells (Sapkota et al, 2020). Thus, CSAG1 may function to ensure proper cell division upon CSAG2 downregulation of p53.…”

Section: Of 16mentioning

confidence: 73%

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CSAG2 is a cancer‐specific activator of SIRT1

Potts

2020

EMBO Reports

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SIRT1 is a NAD+‐dependent deacetylase that controls key metabolic and signaling pathways, including inactivating the p53 tumor suppressor. However, the mechanisms controlling SIRT1 enzymatic activity in the context of cancer are unclear. Here, we show that the previously undescribed CSAG2 protein is a direct activator of SIRT1. CSAG2 is normally restricted to expression in the male germline but is frequently re‐activated in cancers. CSAG2 is necessary for cancer cell proliferation and promotes tumorigenesis in vivo. Biochemical studies revealed that CSAG2 directly binds to and stimulates SIRT1 activity toward multiple substrates. Importantly, CSAG2 enhances SIRT1‐mediated deacetylation of p53, inhibits p53 transcriptional activity, and improves cell survival in response to genotoxic stress. Mechanistically, CSAG2 binds SIRT1 catalytic domain and promotes activity independent of altering substrate affinity. Together, our results identify a previously undescribed mechanism for SIRT1 activation in cancer cells and highlight unanticipated approaches to therapeutically modulate SIRT1.

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Section: Of 16mentioning

confidence: 73%

“…CSAG2 is necessary and sufficient to drive cell and tumor growth CSAG1 has previously been suggested to play a role in mitotic progression (Sapkota et al, 2020). Therefore, we focused our study on CSAG2 that has not been previously characterized.…”

Section: Csag Genes Are Aberrantly Expressed In Cancer and Correlate mentioning

confidence: 99%

CSAG2 is a cancer‐specific activator of SIRT1

Potts

2020

EMBO Reports

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“…For instance, centrosome defect is known to result in ICSI failure because this cellular component is involved in control of the rst division after fertilization (Toure et al 2021). In case 21C0764, CSAG1 was hemizygously deleted, depletion of which disrupts centrosomes and leads to multipolar spindles during mitosis (Sapkota et al 2020). Therefore, information regarding failure of ICSI is also important for counseling with NOA patients.…”

Section: Discussionmentioning

confidence: 99%

“…The protein of FATE1 is known to control the early testicular differentiation and cell proliferation, and high expression of gene FATE1 was only observed in Sertoli cells (Figure 2A) in early testicular development. In comparison, depletion of CSAG1 disrupts centrosomes and leads to multipolar spindles during mitosis (Sapkota et al 2020), but no expression of gene CSAG1 was identi ed from fetuses (Figure 2A). Both FATE1 and CSAG1 are highly expressed in adult germ cells (Figure 2B and C).…”

Section: Cohort Characteristics and The Landscape Of Genomic Variantsmentioning

confidence: 97%

Mate-pair genome sequencing reveals structural variants for idiopathic male infertility

et al. 2022

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Currently, routine genetic investigation for males with infertility includes karyotyping analysis and PCR for Y chromosomal microdeletions to provide prognostic information such as sperm retrieval success rate. However, over 85% of the cases remain idiopathic. We assessed 101 males with primary infertility in a retrospective cohort analysis who have previously received negative results from standard-of-care tests. Mate-pair genome sequencing (with ~ 5kb DNA fragment-size), an alternative long-DNA sequencing method was performed to detect clinically signi cant structural variants (SVs) and copy-number neutral absence of heterozygosity (AOH). Candidate SVs were ltered against our in-house cohort of 1,077 fertile men, and potentially clinically signi cant variants were correlated with gene expression pro les from single-cell RNA-seq datasets that curated human fetal and postnatal testicular development and adult germ cells. Follow-up studies were conducted for each patient with clinically relevant nding(s). Molecular diagnoses were made for 15.9% (10/63) of patients with non-obstructive azoospermia and 21.1% (8/38) of patients with severe oligozoospermia, respectively. Among them, 17 clinically signi cant SVs were identi ed in 16 cases, including ve well-known syndromes, two inversions, and 10 SVs with direct disruption of genes by intragenic rearrangements or complex insertions. Importantly, a genetic defect related to Intracytoplasmic Sperm Injection (ICSI) failure was identi ed in a non-obstructive azoospermia patient illustrating the additional value of an etiologic diagnosis in addition to determining sperm retrieval rate. Our study reveals a landscape of various genomic variants in 101 males with idiopathic infertility, not only advancing understanding of the underlying mechanisms of male infertility, but also impacting clinical management.

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“…In a recent study, a bioinformatic approach was used to identify novel mitotic components, and subsequent analysis revealed the role of chondrosarcoma-associated gene 1 protein (CSAG1) to be involved in maintenance of centrosome integrity during mitosis. Depletion of CSAG1 led to acentriolar multipolar spindle formation; this was especially pronounced in p53-compromised cells [ 178 ]. Moreover, siRNA-mediated knockdown of CEP164 was also demonstrated to result in the formation of multipolar spindles with acentriolar poles, identifying another protein that induces PCM fragmentation [ 179 ].…”

Section: Centrosome Amplification In Tumors and The Causesmentioning

confidence: 99%

Keep Calm and Carry on with Extra Centrosomes

Kalkan

Özcan

Quintyne

et al. 2022

Cancers

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Aberrations in the centrosome number and structure can readily be detected at all stages of tumor progression and are considered hallmarks of cancer. Centrosome anomalies are closely linked to chromosome instability and, therefore, are proposed to be one of the driving events of tumor formation and progression. This concept, first posited by Boveri over 100 years ago, has been an area of interest to cancer researchers. We have now begun to understand the processes by which these numerical and structural anomalies may lead to cancer, and vice-versa: how key events that occur during carcinogenesis could lead to amplification of centrosomes. Despite the proliferative advantages that having extra centrosomes may confer, their presence can also lead to loss of essential genetic material as a result of segregational errors and cancer cells must deal with these deadly consequences. Here, we review recent advances in the current literature describing the mechanisms by which cancer cells amplify their centrosomes and the methods they employ to tolerate the presence of these anomalies, focusing particularly on centrosomal clustering.

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CSAG1 maintains the integrity of the mitotic centrosome in cells with defective p53

Cited by 8 publications

References 42 publications

CSAG2 is a cancer‐specific activator of SIRT1

CSAG2 is a cancer‐specific activator of SIRT1

Mate-pair genome sequencing reveals structural variants for idiopathic male infertility

Keep Calm and Carry on with Extra Centrosomes

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